Bioactive Materials 53 (2025) 591–629

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Bioactive Materials
journal homepage: www.keaipublishing.com/en/journals/bioactive-materials

Review article

Magnetic nanomaterials for hyperthermia-based therapy and controlled

drug delivery
Yu Chen a,1, Haifu Sun a , Yonggang Li a , Xixi Han a , Yuqing Yang a, Zheng Chen b,
Xuequan Zhao a, Yuchen Qian a, Xishui Liu c , Feng Zhou a,*, Jiaxiang Bai d , Yusen Qiao a
a
Department of Orthopaedics, The First Affiliated Hospital of Soochow University Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215006, Jiangsu,
China
b
School of Clinical Medicine, Capital Medical University, Beijing, 100069, China
c
Department of Breast Surgery, Changhai Hospital, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China
d
Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and
Medicine, University of Science and Technology of China, Hefei, 230022, China

A R T I C L E I N F O A B S T R A C T

Keywords: As an innovative physiotherapeutic approach, magnetic hyperthermia therapy (MHT) has unique advantages
Magnetic hyperthermia therapy including minimal invasiveness, precise temperature control, and deep tissue penetration capabilities. It offers
Magnetic nanoparticles unparalleled control over heating areas and temperatures, boasts high efficiency, and results in excellent tissue
Alternating magnetic field
penetration, while remaining independent of biological tissues. With vast potential in biomedical applications
Biomedical applications
ranging from antitumor therapy to thrombus dissolution, MHT harnesses magnetic nanoparticles (MNPs) to
Drug delivery
Clinical trials convert magnetic energy into thermal energy under an alternating magnetic field (AMF), thereby achieving
therapeutic effects. Advanced magnetic nanocomposite platforms based on magnetic nanoparticles can avoid
various risks associated with traditional tools, achieving precise, on-demand, or continuous targeted drug de­
livery and release through multiple approaches. The potential clinical applications of magnetic hyperthermia
therapy are being progressively developed. The present article presents an exhaustive review of the research
progress in magnetic hyperthermia therapy. Initially, the overall landscape of MHT was outlined, including
physical heat generation mechanisms, types of magnetic nanoparticles and conductive nonmagnetic materials,
strategies to increase the thermal efficiency of MNPs, and experimental evidence and research progress on “hot-
spot” effects. This review has focused on biomedical applications and targeted drug delivery of innovative
combination therapy strategies based on MHT. The progress of clinical trials on MNPs-mediated MHT (MNPs-
MHT) is summarized below. Furthermore, the limitations, major challenges and prospects in the clinical trans­
lation of MHT are discussed. The objective of this work is to provide a panoramic view of biomedical applications
and targeted drug delivery of MHT, which can potentially guide researchers and facilitate the successful
implementation of advanced MNPs-MHT systems in the future.

1. Introduction magnetic energy into heat through Néel-Brownian relaxation under an

AMF. This creates localized temperatures above 42 ◦ C, forming
Thermotherapy has evolved significantly since its ancient origins in high-temperature zones that destroy target tissues. Modern MHT utilizes
tumor management. The origins of magnetic hyperthermia therapy various types of engineered MNPs to enable localized thermal energy
(MHT) date back to 1957, when Gilchrist et al. [1] first used magnetic conversion via AMF [2]. This modality addresses three key limitations of
materials to destroy metastatic lymphoma tissue in dogs via heat gen­ conventional hyperthermia: first, achieving deep tissue penetration in­
eration under an alternating magnetic field (AMF). Briefly, magnetic dependent of optical transparency; second, enabling real-time temper­
nanoparticles (MNPs) act as thermal mediators in lesions and convert ature control through magnetic field modulation; and third, facilitating

Peer review under the responsibility of editorial board of Bioactive Materials.

* Corresponding author.
E-mail addresses: zhoufeng1978@suda.edu.cn (X. Liu), jxbai1995@ustc.edu.cn (F. Zhou), qiaoyusen8612@suda.edu.cn (J. Bai).
1
Co-first authors.

https://doi.org/10.1016/j.bioactmat.2025.07.033
Received 27 April 2025; Received in revised form 21 June 2025; Accepted 18 July 2025
Available online 26 July 2025
2452-199X/© 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y. Chen et al. Bioactive Materials 53 (2025) 591–629

synergistic integration with drug delivery systems. To achieve a tem­ reactive oxygen species (ROS) generation [17]. This subcellular target­
perature greater than 42 ◦ C (43◦ C–46 ◦ C) [3] without affecting sur­ ing enhances therapeutic outcomes, through specific biological mecha­
rounding healthy tissues, a strict restriction of "H × f < 5 × 109 Am− 1 nisms [18]. Moreover, significant progress has been made in targeted
s− 1″ has been imposed on H and f in AMFs for biomedical safety （H is drug delivery and controlled release of magnetic nanoparticle-based
the applied magnetic field intensity and f is the magnetic field fre­ nanomaterials. Clinical trials and clinical translation related to
quency) [4]. This requires improving the thermal conversion efficiency MNPs-MHT also deserve attention.
of MNPs. Recent strategies to increase MHT efficiency include opti­ Recent advancements in nanotechnology and MNP development
mizing MNP size [5], type [6], shape [7], drug loading or specific have revitalized MHT research [19]. A key advantage of MNPs-MHT is
dopants [8], and anisotropy [9], and combining MHT with immuno­ its precise targeting, which enables deep tissue treatment without
therapy, chemotherapy, or photothermal/photodynamic therapy (PDT). harming healthy cells [20]. Unlike infrared or microwave methods,
In addition to direct thermal ablation, MHT can induce tumor cell MHT faces no penetration depth limitations or thermal decay [21].
apoptosis [10], kill bacteria [11], activate immune responses [12], Other benefits include: (1) the absence of physiotherapy-induced drug
stimulate tissue regeneration [13], and dissolve thrombi [14]. Recent resistance [22]; (2) magneto-thermal controlled drug delivery [23,24];
research has shown that MNPs can be cleared via blood circulation or (3) immune system activation for antitumor effects [25]; (4) synergy
phagocytic recognition in the liver, spleen, and lymph nodes posttreat­ with chemotherapy, radiotherapy, and chemodynamic therapy [18]; (5)
ment, minimizing residual accumulation and normal tissue damage nanoscale spatial resolution for localized temperature control [26]; (6)
[15]. Additionally, MNPs-mediated MHT (MNPs-MHT) can induce precise control over heating areas and temperatures via tunable mag­
localized heat at the subcellular level, targeting organelles such as ly­ netic material properties; and (7) noninvasive/minimally invasive
sosomes to trigger cell death via lysosomal pathways [16] or localized application.

Fig. 1. A comprehensive schematic illustration of the designs, fabrication materials of MNPs and conductive nonmagnetic materials, and their biological effects in
different aspects, including antitumor, antibacteria, immunomodulation, tissue regeneration, and thrombolysis.

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This review comprehensively examines the development of magnetic important. However, the macroscopic thermal effects of MNPs under an
hyperthermia therapy by highlighting the types of magnetic nano­ AMF are influenced by multiple factors, including eddy current loss,
particles and conductive nonmagnetic materials, the biological effects of hysteresis loss, and relaxation loss [27,28]. Notably, eddy current loss
multifunctional magnetic nanocomposites, and their applications in under an AMF is negligible in nanosized magnetic materials [29].
targeted drug delivery and controlled release (Fig. 1). Additionally, it Therefore, it is essential to first understand the heat generation mech­
synthesizes the physical heat-generation mechanisms of magnetic hy­ anisms, including hysteresis loss and relaxation loss, of MNPs.
perthermia therapy, methods to increase the magnetothermal conver­ Hysteresis loss primarily arises in multidomain NPs. In ferromagnetic
sion efficiency of MNPs, “hot-spot” effects, and clinical trials. Notably, materials, the magnetic structure naturally divides into distinct do­
this review pioneers a novel classification of MNPs and conductive mains, each characterized by uniformly aligned spins and separated by
nonmagnetic materials on the basis of dominant heat-generation transitional boundaries known as domain walls. Heat generation occurs
mechanisms, while providing a thorough elaboration on the biological when magnetic moment reorientation in nanomaterials lags behind
effects of MHT-centered nanocomposite platforms as well as targeted external field direction changes. This phase lag converts magnetic en­
drug delivery and controlled release. Serving as an interdisciplinary ergy into heat through work performed by the magnetic field. These
roadmap integrating materials science, biomedicine, and clinical med­ hysteresis losses constitute the primary heating mechanism in multi­
icine perspectives, this work systematically consolidates cutting-edge domain MNPs [30] (Fig. 2a). When the material is subjected to a cycle of
magnetic material properties and applications, analyzes their molecu­ magnetic fields, the magnetization shows a nonlinear curve called a
lar/cellular mechanisms in scenarios such as antitumor, antibacteria, hysteresis loop, which is a measure of the energy dissipated per cycle of
immunomodulation, tissue regeneration, and thrombus dissolution, and magnetization reversal. It describes the relationship between magnetic
bridges basic research with clinical translation by analyzing the prog­ field intensity (H) and material magnetization (M) [31]. In hysteresis
ress/limitations of clinical trials and emerging advances such as artifi­ loss, high coercivity (Hc) is a key parameter that measures the ability of
cial intelligence (AI), thereby establishing a forward-looking reference a magnetic material to resist demagnetization. It is defined as the
for promoting innovative development in magnetic hyperthermia strength of the reverse magnetic field that needs to be applied to reduce
technologies. the M of a magnetic material to zero. Hc indicates that a stronger
external magnetic field is required to change the magnetization of the
2. Basic information of MHT material, with significant energy dissipation. (Fig. 2b–d). Super­
conducting quantum interference devices (SQUIDs) measure these loops
The above introduction provides a foundational understanding of and enable the evaluation of MNP stability through
MHT. Below, we outline the general aspects of MHT, including its temperature-dependent magnetization analysis [32]. Notably,
mechanisms, types of MNPs and conductive nonmagnetic materials, and single-domain MNPs, particularly superparamagnetic nanomaterials,
strategies for enhancing MNP thermal efficiency. exhibit zero coercivity due to negligible resistance to magnetization
changes (Fig. 2d) [33]. Therefore, for superparamagnetic nano­
2.1. Macroscopic heat generation mechanism of MNPs materials, instead of being able to generate magnetic energy and thus
convert it into heat through the hysteresis loss mechanism described
Magnetic materials possess distinctive magnetic properties enabling above, the temperature is increased through the Brownian-Néel relax­
remote, noncontact manipulation via magnetic fields. Taking MNPs as ation phenomenon (Fig. 2c) [34].
an example, they are among the most critical components in MHT. MNPs Néel relaxation involves internal magnetic moment reorientation
mediate magnetothermal energy conversion as magnetic nano­ within MNPs, which is dominant in smaller particles. Brownian relaxa­
mediators, thus, enhancing their heat conversion efficiency is critically tion describes physical particle rotation in fluid environments, and is

Fig. 2. Schematic representation of heat generation mechanisms in MNPs. Reproduced with permission [2]. Copyright 2024, The Authors. Published by Elsevier
B.V. (a) Larger multidomain MNPs typically generate heat due to hysteresis losses as a consequence of the motion of the domain walls. (b) Typical hysteresis loop
obtained for multidomain MNPs. (c) Single-domain MNPs can undergo Brownian and/or Néel relaxation. In Brownian relaxation mechanisms, the entire particle
rotates within the fluid, generating energy losses. Néel relaxation processes are related to the rotation of the magnetic moment within the MNP core. (d) Typical
hysteresis loop obtained for superparamagnetic MNPs. M is the magnetization of the material, and H is the applied magnetic field intensity.

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prevalent in larger MNPs or high-viscosity solutions [35]. Theoretical Eddy current loss: When a conductor is placed in an AMF, the eddy
modeling of these thermal conversion mechanisms remains central to current is generated because of two possible causes [28]: (1) variations
optimizing MHT, which achieves therapeutic heating without damaging in the field with time, or (2) relative motion of the field source and
healthy tissues. conductor. When eddy currents flow inside a conductor, heat is gener­
ated according to Joule’s law [28]. Moreover, recent studies have
demonstrated that other conductive nonmagnetic materials can exhibit
2.2. Types of magnetic nanoparticles and conductive nonmagnetic heat generation effects when exposed to an AMF. For example, assem­
materials bled films of gold nanoparticles generate heat via eddy current loss
under an AMF [37]. These conductive nonmagnetic materials with
MNPs are one of the indispensable magnetic nanomaterials for MHT. magnetic field responsiveness may provide new inspirations for
The latest review briefly classifies MNPs according to their composition, advancing MHT across multiple fields, including cancer therapy, bac­
structure, and function [36]. They are mainly classified into magnetic terial infection treatment, immunomodulation, tissue regeneration, and
iron oxide nanoparticles (IONPs), metal magnetic nanoparticles thrombolysis.
(MMNPs), carbide magnetic nanoparticles (CMNPs), rare earth mag­ Consequently, this paper proposes a novel classification of MNPs and
netic nanoparticles (REMNPs), core-shell magnetic nanoparticles, and conductive nonmagnetic materials on the basis of the dominant heat
magnetic nanocomposites (MNCs).

Table 1
Types of magnetic nanoparticles and conductive non-magnetic materials.
Type Mechanism Dominance Application Advanced progress Ref.

Rare earths Hysteresis Excellent magnetic properties Precise heating of tumor tissue, Nd2Fe14B@SiO2 core-shell [39]
Nd2Fe14B NPs loss such as
SmCo5 NPs Hysteresis high remanence and high eliminate bacteria, Structure. [40,41]
Ferrite loss coercivity. magnetic resonance imaging SmCo5/Co magnetic [42–45]
CoFe2O4 NPs Hysteresis High magnetic energy product, (MRI) monitoring. nanocomposite particles. [46,47]
LiFe5O8 NPs loss excellent thermal stability. Some potential for theoretical CoFe2O4-CaCO3 composite, [48,49]
Metal Alloy Hysteresis Adjustable ion ratio, applications that are still being Zn-CoFe2O4@Zn− MnFe2O4-PEG, [50]
L-10 FePt NPs loss excellent heat generating explored. Co0.65Fe2.35O4 (Co-Fe NCs). [51–54]
CoPt NPs Hysteresis capability, Synchronize MHT and controlled PVDF-HFP/Cellulose/LiFe5O8 [55–58]
Iron-based loss mild MHT. drug release, FePt@eHNT, [59,60]
Oxides Hysteresis Reduce damage to healthy immunotherapy of tumors. FePt-Au core-shell NPs, [61,62]
Fe3O4 NPs loss tissue, Effective antibacterial, CoPt/Au nanosheet motor. [64,65]
Mn-based Oxides Relaxation mild MHT. temperature-sensible heat Co doped Fe3O4, [67–69]
MnFe2O4 loss Ultrahigh magnetic anisotropy, therapy. Fe3O4-mPEG2000, [70]
Rare Earth-doped Relaxation enhanced hysteresis loss. Drug delivery, 7-nm Mn0.5Zn0.5Fe2O4 SPIONs, [71]
Gd-doped Fe2O3 loss Adjustable particle size, MHT and bioimaging. mesoporous Fe3O4 Nanoparticles Loaded with IR-
NPs Relaxation optimized structural domain Magnetically guided and light- 820.
Tb-doped Fe3O4 loss structure. triggered drug delivery and R837-OVA-PEG-MnFe2O4 NPs,
NPs, Relaxation Small size, release. CoFe2O4@MnFe2O4 NPs.
Dy-doped Fe3O4 loss superparamagnetic behavior, Tumor growth inhibition, PEGylated Gd-doped iron oxide (PEG-GdIO)
NPs Eddy current large specific surface area, collaborative MRI for therapeutic Multi core-shell Fe3O4@SiO2β-NaGdF4:RE3+ (RE
Metal-based loss good biosafety, diagnosis, = 5 %Ce, 5 % Tb, x%Dy; x = 1,5 and 10 mol.%) NPs
materials Eddy current suitable magnetic crystal destroys biofilm and kills bacteria, Mg:Zn:Ca (97.7:2.0:0.3),
Magnesium- loss anisotropy. targeted drug delivery. Mg@DOX micro-rods.
based materials Eddy current Superparamagnetic behavior, Treatment of bacterial infections, MMSN/GQD,
Carbon-based loss good thermal stability, combination therapy (with Gra-Aga-Drug.
materials Eddy current easy surface modification, immunotherapy, chemotherapy, PPY@Fe3O4 composite NPs
Graphene (Gra)/ loss good biocompatibility. etc.), PANI/γ-Fe2O3 NPs
Graphite Multifunction, biomedical imaging guidance,
Conductive strong paramagnetic force. drug carrier.
Polymers Excellent relaxation response, MRI contrast agent imaging,
Polypyrrole (PPy) precise thermal dose control, hyperthermia for tumors,
Polyaniline good thermal stability, drug carrier,
(PANI) tunable magnetic anisotropy. cell labeling and tracking.
Excellent magneto-thermal Microtumor thermal ablation,
conversion efficiency, rapid localized heat generation to
superior penetration depth, kill bacteria,
high mechanical compatibility, combine with radiotherapy,
excellent biocompatibility and chemotherapy, etc.
biodegradability in vivo. Tumor ablation,
Robust eddy thermal effect, drug carrier,
superior biocompatibility, reduce inflammation,
customizable shapes and sizes, combination therapy strategies.
low cost, Tumor suppression,
large-scale production combination therapy (with
capability. immunotherapy, chemotherapy,
Excellent electrical etc.),
conductivity, controlled drug delivery.
good environmental stability, Magnetically guided thermal
outstanding biocompatibility. imaging,
Unique redox activity, tumor ablation,
adjustable conductivity, synergistic photothermal therapy.
responding to the tumor Inhibit tumor progression and
microenvironment. metastasis,
enhance MRI contrast.

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generation mechanism. They are systematically categorized into three electromagnetic energy into thermal energy through the Néel or Brow­
main types of material systems: hysteresis loss-dominated nanoparticles, nian relaxation mechanism under thermal perturbation, which is suit­
relaxation loss-dominated nanoparticles and conductive nonmagnetic able for low-field, high-frequency MHT scenarios.
materials dominated by eddy current loss. Each type of system contains Iron-based oxides: Magnetite (Fe3O4) is one of the most representa­
a dominant loss-heat generation mechanism, a rich variety of materials tive materials in this category. Fe3O4 has suitable magnetic crystal
and unique performance advantages, laying a solid foundation for the anisotropy for efficient magnetothermal conversion via relaxation loss.
precise and efficient application of MHT. A brief overview is provided This material inherently has a large specific surface area, leading to an
below, categorizing types of MNPs and conductive nonmagnetic mate­ accelerated magnetic relaxation process. An appropriate concentration
rials by their dominant mechanism, and highlighting their advanced of cobalt resulted in better magnetic anisotropy and greater thermal
progress. Representative MNPs and conductive nonmagnetic materials efficacy of the Fe3O4 nanoparticles [51]. The precise tuning of the
are listed in Table 1. nanoparticle size and polyethylene glycolization modification of the
surface (Fe3O4-mPEG2000; FP) can lead to more effective tumor growth
2.2.1. Hysteresis loss-dominated nanoparticles inhibition in vivo. The results showed that smaller FPs (<8.5 nm)
Such materials need to have high coercivity and magnetic anisot­ generate negligible heat and are therefore not suitable for MHT, whereas
ropy, and energy dissipation is achieved by irreversible displacement of FPs with a diameter of 13.5 nm showed significant synergistic anticancer
magnetic domain walls with magnetic moment steering. effects in MHT and effective T2-weighted MRI with minimal side effects
Rare earth permanent magnets: Represented by magnetic NdFeB [52]. Recently, researchers have developed 7-nm Mn0.5Zn0.5Fe2O4
nanoparticles (Nd2Fe14B), this material inherently possesses excellent SPIONs that can significantly enhance antitumor immunity while
magnetic properties such as high remanence and high coercivity [38]. In enhancing T2 contrast and magnetothermal properties for optimal
Nd2Fe14B@SiO2 core-shell structures, the introduction of a silica shell therapeutic diagnostic outcomes [53] and mesoporous Fe3O4 nano­
effectively isolates the core from external environmental corrosion, particles containing IR-820 can achieve dual antimicrobial activity by
whereas the presence of functional groups such as -OH significantly combining the high temperature of MHT with the release of ROS from
enhances biocompatibility [39]. The samarium-cobalt (SmCo) series photodynamic therapy [54].
also demonstrated exceptional performance. Owing to their high mag­ Manganese-based oxides: Manganese ferrite (MnFe2O4), with its low
netic energy product and superior thermal stability, SmCo5 nano­ Curie temperature, exciting magnetic properties, high chemical stability
particles maintain stable magnetic properties even in high-temperature and excellent biocompatibility, is ideal for localized mild hyperthermia,
environments [40]. By doping with Co, these nanocomposite particles achieving tumor cell ablation without damaging surrounding healthy
substantially increase coercivity and optimize hysteresis loss perfor­ tissues [55,56]. When PEGylated MnFe2O4 NPs are encapsulated with
mance [41]. ovalbumin (OVA) and loaded with the R837 immune adjuvant
Ferrite: In cobalt ferrite (CoFe2O4), the Co2+ ion concentration plays (R837-OVA-PEG-MnFe2O4 NPs), they can be used in conjunction with
a pivotal role in tuning magnetic anisotropy. By optimizing the ion ratio, MHT and immunotherapeutic therapy to treat breast cancer [57]. The
its hysteresis-mediated heat generation capability can be significantly synthesized monodisperse high-performance superparamagnetic
enhanced [42]. When composited with polyethylene glycol (PEG), the CoFe2O4@MnFe2O4 NPs can also be used for the combined treatment of
hydrophilic long chains of PEG effectively mitigate particle agglomer­ MHT and immunotherapy [58].
ation, improving dispersion stability and biocompatibility in biological Rare Earth-doped Systems: Gadolinium-doped iron oxide (Gd-doped
environments [43]. Notably, the synthesis of CoFe2O4-CaCO3 nano­ Fe2O3) is a multifunctional material in which Gd3+ ions, with multiple
composite particles has great potential for use in synchronized magnetic unpaired electrons, exhibit strong paramagnetism. This dual function­
hyperthermia and drug release applications [44]. Recently developed ality enables simultaneous magnetic hyperthermia and MRI contrast
cubic-shaped cobalt ferrite nanoparticles with a Co0.65Fe2.35O4 (Co-Fe imaging, allowing real-time monitoring of therapeutic outcomes [59].
NCs) stoichiometry have an specific absorption rate (SAR) of 400 W/g, For example, PEGylated Gd-doped iron oxide (PEG-GdIO) NPs have
which is twice the SAR of cubic-shaped iron oxide nanoparticles (IONCs) been investigated as contrast agents for glioma imaging. In combination
[45]. Lithium ferrite (LiFe5O8), distinguished by its low Curie temper­ with its MHT properties, it has great potential for use as a diagnostic and
ature and unique hysteresis loop, is particularly suitable for therapeutic agent for gliomas [60]. Terbium-doped magnetite (Tb-do­
temperature-sensitive hyperthermia applications [46]. It achieves ped Fe3O4), and dysprosium-doped ferrite (Dy-doped Fe3O4) leverage
effective treatment under mild thermal conditions while minimizing magnetic coupling between rare-earth ions and host matrices to finely
damage to surrounding healthy tissues. A nanocomposite fiber system, tune magnetic anisotropy and relaxation dynamics [61]. These materials
comprising poly(vinylidene fluoride cohexafluoropropylene) demonstrate exceptional relaxation responses under high-frequency
(PVDF-HFP), microcrystalline cellulose (MCC), and LiFe5O8 nano­ fields. This makes them ideal for precise thermal dose control in
particles, has potent bacteriostatic effects [47]. microtumor ablation, thus enhancing treatment efficacy. Moreover, it
Metal Alloy: The ordered L10 structure of iron-platinum (FePt) en­ has shown outstanding potential for medical hybrid imaging [62].
dows it with ultrahigh magnetic anisotropy. When processed into
nanoparticles, surface effects and quantum confinement further enhance 2.2.3. Eddy current loss-dominated conductive materials
hysteresis loss [48]. The FePt nanoparticles and etched HNTs (eHNTs) Highly conductive metal, nonmetal or polymeric materials generate
are composited by vacuum decompression and the resulting product is closed-loop electric currents via electromagnetic induction, enabling
named FePt@eHNT. It has a saturation magnetization strength of up to efficient heat generation. This mechanism is particularly suitable for
23.769 emu/g, which is higher than that of the composite materials scenarios requiring rapid heating or complex in vivo MHT
studied in previous studies [49]. Cobalt-platinum (CoPt) optimizes environments.
domain structures through precise control of particle size and Metal-based materials: This section introduces mainly magnesium-
morphology, significantly improving hysteresis-mediated heat genera­ based materials. Pure magnesium itself is nonmagnetic. Magnesium al­
tion. By forming heterostructures with gold nanoparticles, CoPt retains loys (MgAs), with their low elastic modulus, high mechanical compati­
magnetic hyperthermia functionality while integrating the optical and bility, and excellent biocompatibility and biodegradability in vivo, are
electrical properties of Au for effective drug delivery and light-triggered widely used clinically as implant metals. Owing to their low electrical
drug release [50]. resistivity, their thermal effect generated through eddy current loss is
remarkably powerful [63]. Therefore, these materials can be implanted
2.2.2. Relaxation loss-dominated nanoparticles into tumors for MHT tumor ablation. By targeting this property of MgA,
Superparamagnetic iron oxide nanoparticles (SPIONs) convert researchers have explored the current thermal effect and tumor ablation

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efficacy of Mg:Zn:Ca (97.7:2.0:0.3) [64]. They ultimately demonstrated hyperthermia therapy, it should be emphasized that MNP heating results
that nonmagnetic, biodegradable MgA is an effective magnetic thermal from synergistic contributions of multiple mechanisms, including hys­
agent for tumor thermotherapy under low-intensity AMF. The teresis and relaxation losses. However, under hysteresis-dominated
AMF-induced heating effect originating from eddy current loss appears conditions—within an optimized parameter window matching MNP
to depend on the length and diameter of the MgA rod. Moreover, Yang magnetic properties, biocompatibility thresholds, and tissue toler­
et al. [65] fabricated magnesium@doxorubicin (Mg@DOX) microrods ance—an increase in particle magnetization M and the application field
by electrospinning technology, which exhibited a significant magnetic intensity H progressively expands the hysteresis loop area. Conse­
field strength-dependent temperature increase under an AMF. This quently, this drives a corresponding increase in the per-cycle thermal
phenomenon originates from eddy current loss. The microrods exhibited output “A”. Based on experimentally validated findings,
good thermal stability, excellent magnetothermal conversion efficiency,
superior penetration depth, and favorable combination therapeutic ef­ SAR = A f [31] (1)
fects. Intriguingly, nonmagnetic liquid metals such as gallium-indium Therefore, under an alternating magnetic field with fixed H and f, the
liquid metals can efficiently heat up under low-field-strength AMF, SAR of identical magnetic iron oxide nanoparticles exhibits a positive
making them suitable for AMF-induced tumor hyperthermia. This pro­ correlation with their magnetization M. Additionally, SAR is influenced
vides a novel strategy for AMF-based tumor thermoablation [66]. by multiple parameters, including size and anisotropy of MNPs, fre­
Carbon-based materials: Graphene, a quintessential two-dimensional quency and amplitude of the applied AC magnetic field, etc. Moreover,
carbon material, possesses ultrahigh conductivity and specific surface the Néel relaxation mechanism is exponentially governed by magnetic
area [67]. The appropriate assembly, processing, and surface modifi­ anisotropy and particle volume, becoming dominant under high-
cation of graphene can result in superior MHT capabilities. For example, frequency magnetic fields and in smaller nanoparticles. In contrast,
magnetic mesoporous silica nanoparticles (MMSNs) can serve as both Brownian relaxation is dependent on hydrodynamic size, prevails in
drug carriers and magnetic heat sources, whereas graphene quantum larger particles and is strongly influenced by the viscosity of the sur­
dots act as capping agents and photothermal generators. Integrating rounding medium. Notably, Brownian losses occur not only in super­
these components enables the synthesis of a multifunctional platform, paramagnetic nanoparticles but also in other systems where sufficiently
graphene quantum dot-capped magnetic mesoporous silica nano­ low viscosity permits full particle rotation [73]. Overall, to optimize
particles, that combines controlled drug delivery, MHT and photo­ heat conversion efficiency of MNPs, strategic tailoring of nanoparticle
thermal therapy [68]. In addition, a graphite-agarose gelatin-drug properties (type, loading or dopants, size, shape and anisotropy) com­
(Gra-Aga-Drug) implant loaded with chemotherapeutic and immuno­ bined with optimizing magnetic field parameters (intensity, frequency)
therapeutic drugs can trigger powerful magnetothermal ablation and an can synergistically enhance thermal performance.
antitumor immune response, ultimately effectively ablating the primary Selection of the appropriate material type: Given the limited mag­
tumor and inhibiting the growth of distant tumors [69]. netothermal heating capability and potential toxicity of metal ions in
Conductive Polymers: Polypyrrole (PPy), owing to its excellent metallic-based magnetic materials, graphite has been proposed as a
conductivity and environmental stability, can encapsulate or coat promising candidate for tumor magnetic hyperthermia. Unlike metallic
magnetic nanoparticles via chemical or electrochemical methods to magnetic systems, graphite leverages its exceptional electrical conduc­
form core-shell or composite structures. Under an AMF, the conductive tivity to generate robust eddy current-induced thermal effects, resulting
network of PPy results in eddy current loss, whereas the embedded in exceptional magnetothermal heating capabilities [67] (Fig. 3a). The
magnetic nanoparticles provide magnetic guidance for targeted hyper­ study demonstrated that within the safety thresholds of MHT, the
thermia. For example, PPY@Fe3O4 composite nanoparticles can be used magnetothermal heating performance of graphite is proportional to both
as multifunctional probes for MRI, thermal imaging, and photothermal its size and the H × f product across a defined operational range
ablation of cancer cells [70]. Polyaniline (PANI), another widely used (Fig. 3b). Under ultralow field conditions (H × f = 0.63 × 109 Am− 1
conductive polymer, exhibits tunable conductivity across pH environ­ S− 1), GRA achieved a 13.7 ◦ C temperature rise in 3 min within
ments due to its unique redox activity. When hybridized with magnetic high-conductivity saline (Fig. 3c), outperforming CoFe2O4 NPs at
nanoparticles, PANI synergistically enhances eddy current loss during equivalent fields. Furthermore, composite materials composed of
magnetic hyperthermia. Additionally, its functional design enables graphite/graphene and other magnetic materials have also demon­
responsiveness to tumor microenvironments and improved therapeutic strated enhanced heat conversion efficiency and additional biological
precision. Specifically, relevant studies have shown that functions. The SPION quantum dot (Fe3O4)/reduced graphene oxide
polyaniline-coated iron oxide nanoparticles (PANI/γ-Fe2O3 NPs) can (Fe3O4/RGO) composite material, developed via the coprecipitation
reprogram tumor-associated macrophages (TAMs) and modulate the method, enables precise control of the Fe3O4 nanoparticle size within
tumor microenvironment to an antitumor profile to inhibit breast cancer the quantum dot range (≤10 nm). When dispersed in acidic pH buffer
progression and metastasis [71]. (pH 4.66), the Fe3O4/RGO composite exhibited a significant thermal
effect [74].
2.3. Improved methods of magnetic nanomaterials Drug loading and specific dopants: Wang et al. [75] developed an
injectable ZnFeO MNP-loaded hydrogel (NO-Gel) with thermosensitive
The heat conversion efficiency of MNPs in fluid media is evaluated poly(ethylene glycol)-polypeptide copolymers (Fig. 3d). This system
through the SAR, which describes the heat generated per unit mass of significantly avoids heat loss caused by multiple injections and enables
magnetic nanoparticles over time under an AMF with a specified fre­ repeated MHT sessions to inhibit tumor autophagy through a single
quency and amplitude [72]. As the SAR describes thermal conversion injection by maintaining homogeneous NP distribution and stability via
efficacy, it serves as a critical metric for determining the therapeutic sol-gel transitions. Multiple approaches have been investigated to
doses required to reliably deactivate target cells in tumors or specific improve the thermal efficiency of standard spherical iron oxide nano­
tissues. Materials exhibiting high SAR values thereby enable minimi­ particles in MHT [76–78]. One common method involves incorporating
zation of the required MNP dose for clinical efficacy. When subjected to transition metal dopants such as cobalt (Co) and manganese (Mn) [76,
an alternating magnetic field with frequency f and amplitude parameter 77,79]. Pioneering advancements in nanoparticle heating performance
μ0Hmax (where μ0 denotes vacuum permeability and Hmax represents the were achieved by Lee et al. [80], who engineered IONPs featuring a Co
maximum value of the magnetic field intensity), magnetic nanoparticles doped core and Mn-doped outer layer. These particles showed a
generate thermal energy “A” per cycle via hysteresis loss mechanisms. remarkable SAR of 2280 Wg-1 under AMF conditions of 500 kHz and
Quantitatively, “A” equates to the hysteresis loop area of the nano­ 37.3 kA m− 1. Later, Jang et al. [81] introduced superparamagnetic
particle assembly [31]. In biomedical applications such as magnetic

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Fig. 3. Strategies for optimizing magnetic nanomaterial thermal efficiency. (a) Schematic illustration of nonmetallic graphite-based tumor hyperthermia
system. Reproduced with permission [67]. Copyright 2024, Elsevier Ltd. All rights reserved. (b) Size-dependent heating profiles of Gra cubes with different sizes
(length of side: 2 mm, 2.5 mm, 3 mm) in AMF. Reproduced with permission [67]. Copyright 2024, Elsevier Ltd. All rights reserved. (c) Magnetic field intensity effects
of heating curves of Gra cubes (length of side: 2 mm) under the AMF with different powers (Happl⋅fappl = X × 109 A m− 1 s− 1, X = 0.63, 0.95, 1.26). Reproduced
with permission [67]. Copyright 2024, Elsevier Ltd. All rights reserved. (d) Schematic illustration of the fabrication of MNPs@NO-Gel and the mechanism of released
NO from MNPs@NO-Gel to enhance the efficacy of mild MHT through inhibiting autophagy. Reproduced with permission [75]. Copyright 2024, The Authors.
Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. (e) (1) The Magnetic hysteresis loops of MZFC with different contents of MWCNTs in
TCA = 700 ◦ C. (2) The Magnetic hysteresis loops of MZFC with 2 wt% of MWCNTs in different TCA (300 ◦ C,500 ◦ C,700 ◦ C and 900 ◦ C). The inset is the photograph of
MZFC-2–700 nanocomposites dispersed in 5 mL of deionized water in the absent (left) and presence (right) of the application of an external magnet. Reproduced with
permission [82]. Copyright 2022, Elsevier B.V. All rights reserved. (f) The heating efficiency of MIONs in both the superparamagnetic and ferromagnetic regimes
in-creased with size. In particular, the 40 nm ferromagnetic NPs have an SAR value approaching the theoretical limit under a clinically relevant AMF. Reproduced
with permission [87]. Copyright 2017, American Chemical Society. (g) M − H curves of cube and sphere measured at 300 K using SQUID. M of cube is 165 emu/g (Fe
+ Zn), and that of sphere is 145 emu/g (Fe + Zn). Reproduced with permission [91]. Copyright 2012, American Chemical Society.

γ-Fe2O3 NPs doped with Mn, which generated nearly three times the described. For example, doping with multiwalled carbon nanotubes
heating capability of the earlier core‒shell design. Both nanoparticle (MWCNTs) initially increases M, peaking at 90.6 emu/g with 1.0 wt%
types displayed potent tumor-suppressing effects when delivered via doping, before decreasing at higher concentrations (Fig. 3e) [82].
intratumoral injection. In addition, the effect of dopants on M has been However, enhanced MHT performance was observed when SPIONs

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doped with magnesium, Mn, or zinc were used, which presented higher significant advancements driven by various cutting-edge technologies
M values than their undoped counterparts did [83]. Intriguingly, 15 nm and innovative approaches, their inherent low heating efficiency under
Zn-doped Fe3O4 NPs presented a 68 emu/g increase in M over that of clinically safe magnetic field parameters remains a major barrier to
pure Fe3O4 and polymer-coated Zn-doped Fe3O4 NPs achieved an SAR widespread clinical adoption. This requires high MNP doses (typically
value of 743.8 W/g, surpassing that of commercial reagents [84]. 1–2 mol/L, several orders of magnitude higher than those used in MRI
Compared with that of pure Fe3O4, the SAR of Gd-doped iron oxide is contrast agents), and thermocouples (invasive) or luminescent ther­
fourfold greater [85]. mometers (remote sensing) must be positioned near tumor sites to pre­
Size and magnetic field parameters: H and f critically affect the vent thermal damage to adjacent healthy tissues [93]. Extensive
heating efficiency. Increasing frequency enhances thermal conversion research has traditionally focused on the inductive heating effects of
within optimal ranges, whereas particle size critically influences per­ uniformly dispersed MNPs across macroscopic volumes. Recent studies,
formance—SAR values initially rise with larger MNPs but decline however, have revealed that individual particles can generate highly
beyond size thresholds [86]. These parameters interact dynamically. localized heat at the nanoscale, known as the "hot-spot effect" [94,95].
Bao et al. [87] reported that the SAR values for MNPs >20 nm exceed This discovery opens new avenues for the future application of
linear theory predictions, with the efficiency increasing in both the MNP-based MHT.
superparamagnetic and ferromagnetic regimes. Notably, 40 nm ferro­ The "hot-spot” effect refers to instantaneous heating characterized by
magnetic MNPs achieved near-theoretical SAR limits under clinically a specific temperature distribution localized in the vicinity of nano­
applicable AMFs (Fig. 3f), allowing efficient tumor heating at minimal particles (or nanoscale components), which results in minimal to no
doses. Ferrero et al. [88] identified peak SAR values (>1100 W/g) using long-range (macroscopic) effects [94]. This approach has its own unique
20 nm MNPs at f = 1 MHz, H20 = 5 kAm− 1 or 30 nm MNPs at f = 500 kHz, advantages [96–98]. First, the “hot-spot” effect reduces the dependence
H20 = 10 kAm− 1. Larger MNPs (40 nm) at lower f = 100 kHz and higher on high-concentration MNPs. This is achieved by generating transient
H20 = 50 kAm− 1 yielded a reduced SAR (~300 W/g). These experiments high-temperature microenvironments within nano- or subnanoscale re­
demonstrate that optimizing the synergistic interplay between nano­ gions around nanoparticles for therapeutic efficacy. This method
particle size and magnetic field parameters can maximize the SAR value, simultaneously lowers the biological burden, environmental impact and
thereby facilitating efficient MHT. toxicity risks. Second, near nanoparticle surfaces, temperatures spike
Adjustment of shape and anisotropy: The anisotropy exhibited by within nanoseconds ("thermal spikes"), while dropping rapidly just
MNPs serves as a critical factor in regulating MHT performance. micrometres away. This creates steep nanoscale temperature gradients,
Following linear response theory, this property significantly contributes enabling precise control over drug delivery and triggered release.
to improving Néel relaxation processes [89]. Common forms of anisot­ Additionally, the effect directly disrupts subcellular structures through
ropy observed in MNPs include surface-related anisotropy, magneto­ spatially specific localized hyperthermia. In contrast, macroscopic
crystalline anisotropy and shape-dependent anisotropy, with the latter heating relies on cumulative thermal effects to induce holistic apoptosis.
two demonstrating particular significance in nanoparticle systems. Furthermore, localized heat production occurs instantly and functions as
Magnetocrystalline anisotropy originates from spin‒orbit coupling ef­ a "molecular switch" to control the activity of interacting molecules,
fects, whose intensity varies with material composition, thermal con­ facilitating targeted disease therapy. Finally, modifying nanoparticles
ditions, and impurity content. As the nanoparticle dimensions decrease, with targeting ligands (e.g., mitochondria-targeting peptides) allows
the proportion of surface atoms relative to bulk atoms increases, leading "precision thermal ablation at the subcellular level". This further mini­
to increased contributions from surface magnetization mechanisms. mizes damage to surrounding healthy tissue.
Under such conditions, surface anisotropy may surpass both magneto­
crystalline and shape anisotropy in its influence on MNP behavior [31]. 3.2. Experimental studies of the “hot-spot” effect
The thermal conversion performance of spherical IONPs has been
extensively investigated. To optimize the anisotropy and enhance the 3.2.1. Indirect experimental studies
heating efficacy, nonspherical IONP geometries such as hexagonal, The “hot-spot” effect necessitates verification of the heating effi­
cubic, octopod, and clover-like structures have been developed [90]. ciency at the nanoscale locality. Supporting data may utilize indirect
Cheon et al. [91] reported that cubic MNPs exhibit higher Mvalues than techniques or direct quantification of the thermal gradient across a
their spherical counterparts because of increased surface anisotropy specified area.
(Fig. 3g). The magnetic force peak at 60 nm (single-to-multidomain Most indirect evidence is confirmed by thermosensitive reactions.
transition) was corrected, whereas the core-shell cubic MNPs achieved a The Diels-Alder (DA) reaction is known as a thermally reversible reac­
14× greater magnetic force and SAR (10,600 W/g), doubling the per­ tion between a diene and a dienophile (an alkene derivative), forming a
formance of commercial Fe3O4 performance. Recent studies have cycloadduct via a clean and straightforward click reaction. This process
demonstrated that nonoctopod Fe3O4 nanoparticles achieve superior typically requires temperatures (90–110 ◦ C) that are incompatible with
heating performance compared with that of spherical variants, partic­ biological applications. However, N’Guyen et al. [99] hypothesized an
ularly under high-field conditions (>400 Oe). Furthermore, Liu et al. approach to introduce sufficient energy near the cycloadduct to trigger
engineered clover-shaped, cobalt-doped IONPs with significantly the retro-DA (rDA) reaction. They described the occurrence of rDA on
improved heat generation capabilities [78]. Cutting-edge research has multifunctional-ligand-functionalized maghemite nanoparticles under
also revealed the importance of nanoparticle shape. To overcome limi­ AMF exposure, leading to the release of conjugated fluorophores. This
tations in systemic magnetic hyperthermia for complete tumor sup­ multifunctional ligand utilizes maleimide linked to a furan-terminated
pression, Singh et al. [92] engineered cobalt-doped iron oxide moiety as a thermosensitive linker. The ligand is designed to provide a
nanoparticles (Co-IONPs) featuring a cubic bipyramid morphology. cleavable bond in immediate proximity to the MNP surface. The results
These nanostructures demonstrated record-high heating performance, revealed significantly greater fluorophore release in the AMF-exposed
achieving an SAR of 14,686 ± 396 W/g, nearly double the 7490 ± 306 group than in the control group with no increase in the macroscopic
W/g reported for earlier core-shell nanoparticle designs. temperature. This indirectly verifies the “hot-spot” effect in maghemite
nanoparticles. Rühle et al. [100] utilized the same rDA reaction to
3. “Hot-spot” effect monitor MHT on (Zn0.4Mn0.6)Fe2O4 nanoparticles loaded within
mesoporous silica nanoparticles. These nanoparticles were sealed by
3.1. The concept and advantages of the “hot-spot” effect molecules that served as nanovalves and could be triggered via thermal
response. The results demonstrated that molecular release occurred
While the heat conversion efficiency of MNPs has undergone above 65 ◦ C, whereas the bulk solution temperature remained nearly

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constant. This indicates that localized heat generation is confined to the method involved physical separation between the nano-heater (MNP)
nanoscale region surrounding the core-shell nanoparticles. Mai et al. and nanothermometer (GFP). In a very recent investigation, Gu et al.
[101] also developed clickable polymer ligand-functionalized iron oxide [125] constructed both types of heater/thermometer nanostructures to
nanocubes via a DA reaction. This composite enabled localized “hot-­ compare differences in intracellular temperature increases and validate
spot”-mediated drug liberation under magnetic stimulation. Iron oxide the feasibility of the “hot-spot” effect. The single-particle configuration
nanoparticles modified with molecularly imprinted polymers were features heater-thermometer core@shell nanoparticles with γ-Fe2O3
implemented by Griffete et al. in drug delivery systems [102]. A sig­ cores and polymer coatings embedding Sm3+/Eu3+ complexes. This
nificant increase in doxorubicin release occurred following AMF stim­ ratiometric luminescent sensing platform enables nanoscale surface
ulation. Liberation rates mirrored those attained above 50 ◦ C, enabling temperature measurements during intracellular heating events. Simi­
assessment of the mean temperature of the polymer corona adjacent to larly, the dual-particle approach employs nonconjugated Sm3+/Eu3+
the magnetic core (10–30 nm range). Cazares-Cortes et al. [103] also thermometric nanomicelles with γ-Fe2O3 MNPs to quantify
reached similar conclusions. Very recent studies have further confirmed AMF-induced thermal elevations in both intracellular and extracellular
the existence of the “hot-spot” effect. Chen et al. [104] designed environments. When exposed to an AMF, negligible changes in the
core@shell MnFe2O4@CoFe2O4@MSN nanoparticles loaded with the extracellular temperature occurred with both methods. However, the
fluorescent dye Hoechst. The MSN surface was capped with gatekeeper maximum intracellular temperature increase reached 8.0 ◦ C on the
cyclodextrin via a thermolabile linker. When exposed to an AMF, this surface of the single-particle core@shell nanoparticles, whereas the
linker undergoes irreversible cleavage due to heat generated internally dual-particle system achieved only 5.9 ◦ C and required twice as long to
within the core@shell nanoparticles. The results demonstrated that reach this level. Overall, this research provides further evidence of a
localized heating originating from the nanoparticle cores under AMF “hot-spot” effect.
exposure triggered significantly more efficient Hoechst release than did
bulk heating at 50 ◦ C in a water bath, despite the minimal overall in­ 3.3. Effects of MNPs-MHT at the cellular and subcellular levels
crease in the solution temperature.
Taken together, previous studies have indirectly confirmed the pos­ Notably, in MNPs-MHT, the application of “hot-spot” effects typi­
sibility of MNPs generate locally induced heat when exposed to AMF. cally employs engineered MNPs that target specific organelles for pre­
cision damage. However, previous studies have focused primarily on
3.2.2. Direct experimental studies exploring the damage mechanisms of MNPs-MHT at the cellular level.
Although the “hot-spot” effect has been indirectly explored through Therefore, investigating the effects of MNPs-MHT at both the cellular
macroscopic observations of effects derived from the nanoscale, there is and subcellular levels along with their inherent discrepancies, is
still a need for direct assessment of the local temperature distribution imperative. The following section details the effects of MNPs-MHT at the
around nanoparticles at the nanoscale. Initially, researchers conducted cellular and subcellular levels, along with advances in cutting-edge
MHT experiments using MNP aqueous suspensions [105–107] and applications. A summary of the different effects of MNPs-MHT at the
powdered dispersions [108] (both in vitro [109] and in vivo [110]). cellular and subcellular levels is presented in Table 2.
They reported localized temperature increase at the MNPs relative to the
bulk water temperature. The emergence of such temperature gradients 3.3.1. At the cellular level
within the MNPs supported the hypothesis of localized thermal effects. At the cellular level, this section elaborates on three principal impact
However, findings from aqueous or powdered suspensions cannot be mechanisms of MHT: cellular proliferation and cycle regulation,
directly extrapolated to cellular environments because of significant apoptosis, and pyroptosis.
differences in heat transfer efficiency and MNP mobility [111]. Conse­ Cellular proliferation and cycle regulation: G2-M arrest refers to a
quently, reliable intracellular temperature measurements are required phenomenon in which cells are blocked during the transition from the
to obtain accurate thermal gradient profiles. This approach is essential G2 phase (late stages of DNA synthesis) to the M phase (mitosis), pre­
for the definitive confirmation of localized heating phenomena. venting normal entry into division and ultimately leading to apoptosis.
Current studies document diverse luminescent intracellular ther­ Dutta et al. [126] constructed pH-sensitive tartaric acid-stabilized Fe3O4
mometers, such as organic dyes [112–115], oligonucleotides [105], magnetic nanocarriers (TMNCs). Through electrostatic interactions,
fluorescent proteins [116,117], polymers [118,119] and nanoparticles DOX was conjugated to the TMNCs to form the DOX-TMNCs. After the
doped with lanthanides [120]. The quantitative evidence from four exclusion of DOX-specific effects, flow cytometry, Annexin V/PI staining
published works confirms the occurrence of intracellular temperature and Western blot analysis were used to confirm that the apoptosis of
measurements during the external application of AMFs. In the first study triple-negative MDAMB-231 cancer cells was mediated via the induction
[113], researchers utilized superparamagnetic ferrite nanoparticles of G2-M arrest and a subsequent increase in the sub-G1 population
targeted to specific proteins located within the plasma membrane of (indicating apoptotic cells with fractional DNA content). During the G1
TRPV1-expressing cells. Heating was achieved by exposure to an AMF phase, cells are dedicated primarily to biomass accumulation and
while using fluorescent groups as molecular thermometers to monitor organelle biogenesis to support subsequent DNA synthesis. Notably, Li
nanoparticle temperature variations. The experimental results indicated et al. [127] innovatively developed injectable magnetic bimetallic
a highly localized temperature increase. However, as the nanoparticles hydrogels (MFO@PEG-Gels) comprising manganese-iron oxide (MFO)
remained anchored to the plasma membrane, they were not internalized nanocubes embedded in PEG. This design overcomes a critical limita­
within the cells. The second investigation employed single-particle tion: conventional cell cycle inhibitors may trigger proliferation and
nanothermometry, utilizing a cyanine dye probe positioned 7 nm from metastasis in melanoma cells. Under an AMF exposure, MFO sustainably
MNP surfaces [121]. This configuration enabled the thermal monitoring releases Mn2+ and Fe3+ ions. Mn2+ impedes the G1/S transition via p27
of lysosome-encapsulated nanoparticles through single-emission detec­ pathway modulation, whereas Fe3+ arrests the G2/M phase by regu­
tion. For the third approach [122], researchers utilized green fluorescent lating polo-like kinase 4 (PLK4) and concurrently suppresses autophagy,
protein (GFP), which is conjugated to actin filaments at controlled dis­ thereby augmenting cell cycle blockade and promoting melanoma cell
tances and separated from MNPs, to measure intracellular temperatures apoptosis (Fig. 4a).
through GFP lifetime decay profiles. Apoptosis: In addition to exerting effects on proliferation regulation
The last two studies [121,122] employed single-particle [123] and and cell cycle progression, MHT concomitantly modulates apoptosis
dual-particle [124] approaches. For these two studies, the single-particle alongside proliferation/cycle control to potentiate tumor cell death. Nica
approach involved chemical bonding between the nanoheater (MNP) et al. [128] developed trimagnetic nanoparticles (TMNPs) with a
and nanothermometer (cyanine dye probe), whereas the dual-particle Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4 core-shell structure, surface-

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Table 2
Different effects of MNPs-MHT at cellular and subcellular levels.
Level Regulation/ Structural Alterations Brief Molecular Mechanisms Ref.
Structure

Cellular level Functional Mild condensation of chromatin with ill-defined nucleolar p27 pathway modulation (G1-S arrest), [126,127]
Subcellular Regulation structures, polo-like kinase 4 (PLK4) pathway modulation (G2-M [128,129]
level Proliferation disordered cytoskeletal arrangement and impaired spindle arrest). [130–132]
inhibition formation, Caspase-9-dependent apoptosis, [135–138]
and cycle loose intercellular junctions. downregulate expression of HSP70, cyclin D1 and Bcl- [140–143]
blockage Formation of apoptotic bodies with phosphatidylserine (PS) 2 proteins,
Induce apoptosis externalization, oxidative stress activates the p53 pathway.
Induce pyroptosis highly condensed chromatin and fragmented nuclear DNA. Caspase-1/GSDMD-dependent pyroptosis,
Subcellular Micropore formation in the plasma membrane with loss of noncanonical pyroptosis activation triggered by
structure membrane integrity, DAMPs or PAMPs.
Mitochondria moderate chromatin condensation and nuclear pore complex Increased generation of cytotoxic hydroxyl radicals
Plasma dilation. (•OH),
membranes Membrane disruption, membrane potential collapse and cristae ROS-dependent apoptosis through mitochondrial
disintegration. pathways.
Disruption of the lipid bilayer results in increased membrane Lipid peroxidation and membrane protein damage.
permeability, accompanied by ion channel dysfunction.
​ Lysosome Lysosomal membrane permeabilization and enzyme leakage. LMP induces hydrolytic enzyme (including cathepsin [146,147]
B) leakage, activating autophagic cell death.

functionalized with prostate cancer (PCa) cell membranes (CMs) and/or cellular energy production and survival, regulate critical processes
LNP1 cell-penetrating peptide (CPP). Their work ultimately demonstrated including apoptosis, signaling, and ROS generation [134]. MNPs-MHT
that combining CM-CPP dual homotypic targeting with AMF respon­ can induce structural disruption of mitochondria and trigger
siveness significantly induced caspase-9-mediated apoptosis in PCa cells. ROS-dependent apoptosis through mitochondrial pathways [135]. The
Furthermore, MHT potentiated by TMNPs elicited reduced expression of Fenton reaction is a well-known catalytic reaction in which hydroxyl
the proliferation marker Ki-67 and diminished the migratory capacity of radicals (•OH) are generated from hydrogen peroxide (H2O2) (typically
surviving tumor cells. In parallel [129], investigators have explored the by Fe(II)/Fe(III)) [136]. In 2007, Fe3O4 nanoparticles exhibiting
impact of MHT on apoptotic pathways. They revealed that MHT not only intrinsic peroxidase-like activity were discovered. These nanozymes
induces apoptosis by downregulating the protein expression of HSP70, catalyze H2O2 decomposition to generate hydroxyl radicals (•OH).
cyclin D1 and Bcl-2 in tumor cells, but also enhances response rates to Under the acidic tumor microenvironment (TME), these iron-based
T-cell-based immunotherapy through the upregulation of PD-L1 expres­ nanomaterials dissolve into ferrous ions (Fe2+). This initiates Fenton
sion. This dual mechanism effectively suppresses both primary and met­ reactions that convert tumor-overexpressed H2O2 into cytotoxic •OH,
astatic tumor growth (Fig. 4b). triggering tumor cell apoptosis and effective tumor suppression [137].
Pyroptosis: Pyroptosis is a unique form of programmed cell death Building on this foundation, Shen et al. [138] developed Ir(III)
Gasdermin (GSDM)-mediated pyroptosis triggers immunogenic cell complex-functionalized MnFe2O4 nanoparticles (Ir@MnFe2O4 NPs)
death by liberating tumor antigens, thereby converting immunologically capable of mitochondrial targeting. Under an AMF, these NPs generated
“cold” tumors into “hot” tumors and increasing immunotherapy efficacy localized hyperthermia, inducing mitochondrial damage characterized
[130]. Han et al. [131] synthesized Zn-doped composite layered double by membrane disruption, membrane potential collapse and crista
hydroxide (Zn-LDH) coatings on magnesium implants via a hydrother­ disintegration. Crucially, glutathione, which is overexpressed in the
mal methodology to construct Zn-LDH@Mg implants. The Zn-LDH@Mg mitochondria of cancer cells, reduces surface-bound Fe(III) to Fe(II).
implants exhibited pronounced eddy current thermal characteristics Excessive Fe(II) accelerated the rate of the Fenton reaction and con­
under AMF exposure, triggering significant augmentation of verted endogenous H2O2 (overexpressed in tumors) into cytotoxic •OH,
caspase-1/GSDMD-dependent pyroptosis in cancer cells (Fig. 4c). This thereby amplifying ROS-dependent apoptosis through mitochondrial
enhancement was predominantly attributable to intensified intracellular pathways.
Zn2+ uptake and AMF-induced aggravation of oxidative stress within Plasma membranes: MNPs-MHT affects plasma membrane perme­
tumor cells. Similarly, Wang et al. [132] engineered a PEGylated ability and disrupts ion channel functionality. Structurally analogous to
platinum-nickel bimetallic “trilobal”-shaped nanostructure (PPTNS) for eukaryotic plasma membranes, bacterial membranes also consist of
efficient pyroptosis-triggered immunotherapy via dual nanozyme phospholipid bilayers and function as selective barriers. Consequently,
catalysis and magnetomechanical oscillation. Under an AMF, thermo­ bacteria serve as well-suited models for investigating MNPs-MHT-
mechanical oscillations at PPTNS acute angles potentiate induced membrane alterations. It has been reported that MHT can
damage-associated molecular patterns (DAMPs) release, activating the effectively destroy bacterial biofilms and improve membrane perme­
caspase-1-NLRP3-GSDMD pathway to amplify cytokine recruitment. ability through an increase in local temperature rise [139]. Shuai et al.
Furthermore, the high surface area of PPTNS and synergistic nanozyme synthesized hard-soft magnetic biphasic CoFe2O4@MnFe2O4 (CF@MF)
catalysis (Ni2+/Ni0, Pt2+/Pt0 active sites) generated ROS as nanoparticles and incorporated them into poly-L-lactide to fabricate
pathogen-associated molecular patterns (PAMPs), which accelerated porous scaffolds via selective laser sintering. These scaffolds demon­
NOD-like receptor NLRP3 oligomerization through pattern recognition strated effective magnetothermal conversion under an AMF exposure,
receptor stimulation. inducing significant bacterial membrane damage characterized by
distinct wrinkling and structural rupture. Concurrently, robust biofilm
3.3.2. At the subcellular level disruption was observed [140]. Furthermore, MHT generates free radi­
At the subcellular level, MNPs engineered for organelle/membrane cals that trigger lipid peroxidation in cell membranes, compromise
targeting typically harness “hot-spot” effects to induce cellular damage. membrane fluidity, and disrupt ion channel functionality – ultimately
MNPs-MHT have a significant effect on these subcellular structures leading to cell death [141,142]. Chen et al. [143] synthesized
[133] (Fig. 4d). This section details three key substructures: mitochon­ cation-conducting TRPV1-ferritin fusion protein nanoparticles. Under
dria, plasma membranes, and lysosomes. AMF exposure, these nanoparticles release substantial amounts of iron
Mitochondria: Mitochondria, which are essential organelles for ions. The liberated iron ions participated in the generation of massive

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Fig. 4. Schematic representation of the different impacts of MNPs-MHT at cellular and subcellular levels. (a) Ion-interferential cell cycle arrest for melanoma
treatment. Reproduced with permission [127]. Copyright 2024, Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica,
Chinese Academy of Medical Sciences. (b) Schematic of the SMSI strategy to prevent tumor proliferation and metastasis. Reproduced with permission [129].
Copyright 2022, Wiley-VCH GmbH. (c) Schematic illustration of synergistic therapy based on Zn-LDH@Mg implants under an AMF. Zn-LDH was synthesized on the
surface of Mg implants by a hydrothermal method to obtain Zn-LDH@Mg implants. The implants exhibited significant eddy-thermal properties, which increased
intracellular Zn2+ uptake, activated the Caspase-1/GSDMD-dependent pyroptosis pathway in cancer cells, and triggered a systemic immune response, effectively
enhancing the therapeutic effects. Reproduced with permission [131]. Copyright 2024, Wiley-VCH GmbH. (d) Cellular and subcellular biological effects derived from
MNPs-MHT. Reproduced with permission [133]. Copyright 2021, The Authors.

amounts of ROS. Both ROS and their induced lipid peroxidation activate engineered MNPs-based nanomaterials enhance therapeutic outcomes.
ion channels, thereby causing overload of intracellular Ca2+. This
overload significantly reduced cell viability. Crucially, no macroscopic 4.1. Antitumor therapy
temperature increase occurred during experiments. This approach mir­
rors prior studies: Yin et al. [144] used calcium nanoparticles coloaded Tumor thermotherapy generally operates within two temperature
with curcumin/transferrin to trigger Ca2+ overload and activate windows [148]. Magnetic thermal ablation (>50 ◦ C) rapidly and
apoptosis pathways. Specifically, Li et al. [145] designed effectively kills tumor cells but can damage surrounding healthy tissues
Kaempferol-3-O-rutinoside (KAE)-incorporated CaCO3 nanosystems to [149]. Mild hyperthermia (41–46 ◦ C) induces cancer cell death while
disrupt calcium homeostasis, amplifying Ca2+ overload-induced cyto­ sparing normal cells, although incomplete tumor eradication often ne­
skeletal collapse and oxidative stress. Collectively, these studies cessitates repeated sessions or combination therapy [150,151]. A key
demonstrate that inducing intracellular Ca2+ overload represents a challenge for MHT is overcoming heat shock proteins (HSPs), which are
promising strategy for cancer treatment. endogenous proteins that stabilize tumor cells under stress and inhibit
Lysosomes: MNPs-MHT triggers lysosomal membrane per­ apoptosis by protecting tissues from thermal damage [152]. Below, we
meabilization (LMP) and enzyme leakage, ultimately leading to cell summarize recent advances in combination therapy based on MHT for
death through nonapoptotic pathways. Lysosomes play critical roles in diverse tumor types.
cellular degradation, apoptosis, and autoimmune responses against
cancer, making them strategic targets for MHT [146]. Recent studies 4.1.1. Breast cancer
have highlighted LMP-mediated lysosomal cell death [147]. Researchers Breast cancer is a common malignancy. Current chemotherapy reg­
modified ferrimagnetic vortex-domain iron oxide (FVIO) with 3,4-dihy­ imens face limitations due to drug resistance in tumor cells and adverse
droxyhydrocinnamic acid (DHCA) to create FVIO-DHCA. These nano­ side effects [153]. Recent studies revealed that combining MHT with
particles were efficiently internalized by mouse hepatoma cells (Hepa chemotherapy enhances therapeutic efficacy while mitigating
1–6), which were primarily localized in lysosomes. chemotherapy-related toxicity. Rui Sun et al. [154] developed a scaffold
Streptavidin-mediated conjugation of FVIO-DHCA with cell-penetrating enabling repeated AMF-triggered hyperthermia and breast tissue
peptides yielded FVIO-CPP, which selectively targeted the cytoplasm via regeneration after tumor ablation (Fig. 5a), achieving synergistic anti­
endocytosis. The experimental results confirmed that cancer effects through controlled MHT and chemotherapy. This scaffold
lysosomal-localized FVIO-DHCA significantly enhanced Hepa 1–6 cell incorporates thermosensitive DPPC (1,2-dipalmitoyl-sn-glycer­
death and effectively induced immunogenic cell death (ICD). Mecha­ o-3-phosphorylcholine) liposomes to encapsulate anticancer drugs
nistically, AMF-induced localized hyperthermia within lysosomes (DOX), Fe3O4 NPs, gelatin (Gel), and polyglutamic acid (PGA), facili­
intensified LMP. This triggered Bid-mediated apoptosis and tating tumor thermal ablation and tissue repair. Specifically, when the
caspase-1-dependent interleukin-1β (IL-1β) secretion. Furthermore, it scaffold is exposed to an AMF, the thermosensitive DPPC liposomes
reduced calreticulin degradation while increasing its surface exposure, enable the controlled release of encapsulated contents at 41◦ C–42 ◦ C
thereby increasing ICD efficacy. Previous studies [121] developed due to the magnetothermal conversion capability of the Fe3O4 NPs. On
gastrin-grafted magnetic nanoparticles specifically delivered to tumor the one hand, the achieved hyperthermia can selectively kill cancer
lysosomes, confirming that Magnetic Intralysosomal Hyperthermia cells; on the other hand, the released DOX exerts a similar therapeutic
(MILH) induces cell death via nonapoptotic pathways. Crucially, local­ effect. This approach achieves synergistic and enhanced therapeutic
ized heating around nanoparticles amplified ROS generation through efficacy by combining MHT with chemotherapy. More intriguingly, the
lysosomal Fenton reactions. MILH subsequently triggered LMP and the released gelatin and PGA can be applied to regenerate adipose tissue
leakage of enzymes (including cathepsin B) into the cytosol. Cathepsin B after tumor ablation. For tissue regeneration after tumor cell ablation,
activated caspase-1 but not apoptotic Caspase-3, thereby executing cell they proposed a folic acid (FA)-functionalized gelatin scaffold hybrid­
death. ized with citrate-stabilized Fe3O4 NPs (FA-gel/FeNP) [155] (Fig. 5b).
In summary, the “hot-spot” effect in MHT refers to localized tem­ The 3D gelatin matrix promotes tissue adhesion via its RGD (Arg-­
perature spikes generated by MNPs under an AMF due to concentrated Gly-Asp) sequence, and then supports adipose tissue formation. Simi­
energy deposition. Extensive experimental evidence confirms that larly, Farcas et al. [156] validated a combination therapy consisting of
controllable heat generation can be achieved through the modulation of MHT and chemotherapy using magnetic liposomes loaded with betulinic
the magnetic field and material parameters. At the cellular level, it acid (BA), a novel anticancer agent, to improve the effectiveness of
regulates proliferation and cell cycle progression while inducing breast cancer treatment. Hsp90, a highly conserved molecular chap­
apoptosis and pyroptosis. Subcellularly, it disrupts organelle structures erone overexpressed in tumors, stabilizes client proteins and shields
and functions to promote the death of diseased cells. This effect chal­ them from therapeutic stress, presenting a major thermotherapy chal­
lenges conventional uniform heating paradigms and establishes a lenge [157]. Inhibiting Hsp90 is thus critical for enhancing chemo­
theoretical foundation for precision thermotherapy. Future research therapeutic efficacy. To solve this problem, Liu et al. [158] developed
should focus on spatiotemporal control of hot-spots, combination ther­ silica-based MNPs(CD44-HSPI/Fe3O4@SiNP) containing a magnetic
apy, and biosafety to advance clinical translation. core (Fe3O4 NPs), chemotherapeutic Hsp90 inhibitors (17-DMAG,
phase II/III), and fluorescently labeled anti-CD44 antibodies targeting
4. Recent advances in MHT-based combination therapy breast cancer stem cells(BCSCs) (Fig. 5c). These multifunctional MNPs
enable: (1) anti-CD44 antibody targeting; (2) AMF-controlled heat-ch­
Despite these advancements, rigorous evaluation of their biological emotherapy synergy; (3) endosomal localization and 17-DMAG release
impacts remains essential. The following section examines how for Hsp90 inhibition; and (4) fluorescent tracking (Cy7, PE, and FITC) of

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Fig. 5. Schematic representation of advanced solutions for magnetic nanomaterials against breast cancer. (a) Composite scaffolds of Gelatin and Fe3O4 NPs
for magnetic hyperthermia-based breast cancer treatment and adipose tissue regeneration. Reproduced with permission [154]. Copyright 2024, Elsevier Ltd. All
rights reserved. (b) Preparation scheme of composite scaffolds and their applications for synergistic treatment of breast cancer with magnetic hyperthermia and
thermosensitive chemotherapy and regeneration of breast tissue. Reproduced with permission [155]. Copyright 2023, Wiley-VCH GmbH. (c) Schematic illustration of
a single antibody-modified drug-loaded magnetic core–shell NPs. Reproduced with permission [158]. Copyright 2019, WILEY-VCH Verlag GmbH & Co.
KGaA, Weinheim.

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MNP internalization and localization. Furthermore, tumor hypoxia [176], necessitates combination strategies. Wu et al. [177] synthesized
driven by oxygen overconsumption and aberrant vasculature exacer­ ZnCoFe NPs encapsulated in PDLLA-PEG, and codelivered with the
bates treatment resistance through ROS-mediated mechanisms [159]. In Hsp70 inhibitor VER155008 for enhanced tumor accumulation. The
a recent study [160], radical precursor (AIPH) and iron oxide nano­ targeting of BBTB overexpressing CXCR4 via AF-NP modulators can
particles were coincorporated within the alginate (ALG) hydrogel. improve the penetration of NPs and VER155008 can inhibit the over­
Under an AMF, IONPs generate localized heat to decompose AIPH, expression of HSP70 in tumors, thereby improving therapeutic efficacy.
producing alkyl radicals that synergize with MHT to induce apoptosis of Increased thermal resistance during MHT also critically impacts thera­
breast cancer cells. This study offers a highly valuable strategy for peutic efficacy. Recent studies [178,179] underscored the critical role of
overcoming tumor hypoxia, while also serving as a candidate formula­ lipid peroxide accumulation in degrading HSPs, and excessive ROS in
tion for alternative noninvasive breast-conserving therapy (BCT). In tumors impaired HSP production. This effectively diminishes the ther­
addition, Ge et al. [161] proposed magnetoelectrodynamic therapy mal resistance during MHT. Significantly, elevated intracellular
(MEDT) using CoFe2O4-BiFeO3 magnetoelectric NPs, which generate redox-active iron amplifies ROS levels via Fenton reactions and triggers
ROS under magnetic fields for enhanced eradication of breast cancer lipid peroxidation, which accelerates ferroptosis. Additionally, direct
cells. inhibition of glutathione peroxidase 4 (GPX4), a specific enzyme that
repairs oxidized lipids, can drive ferroptosis. Given the dual importance
4.1.2. Hepatocellular carcinoma (HCC) of iron in both ferroptosis and MHT, combining these therapies is pro­
Current standard treatments for hepatocellular carcinoma (HCC) jected to substantially increase tumor treatment efficacy. Inspired by
include surgical resection, liver transplantation, and immunotherapy these findings, Chen et al. [180] innovatively engineered an activatable
[162]. Early studies [163] indicated strong association between HCC thermal gel (AAGel) coloaded with RSL3 (a potent ferroptosis inducer
and chronic inflammation or an immunosuppressive TME. This corre­ that inhibits GPX4) and Zn0.4Fe2.6O4 nanocubes. Upon AMF exposure,
lation was further supported by clinical data [164]. These findings the heat generated by the nanocube rapidly induces sol‒gel transition of
support the rationale for the application of MHT in HCC treatment. the hydrogel, enabling uniform anchoring and prolonged retention of
Building on the immune-evasion mechanisms of HCC cells, particularly the MNPs at tumor sites. Moreover, endogenous arachidonic acid (AA)
macrophage phagocytosis avoidance via the CD47-SIRPα axis [165], or AA-modified polymers potentiate lipid peroxide generation and
Wang et al. [25] developed subferromagnetic vortex-domain iron oxide intensify RSL3-triggered ferroptosis. In addition, improving the tumor
(FVIO)-mediated MHT. This strategy disrupts CD47-SIRPα signaling targeting ability of magnetic nanocomposites is also crucial for
while promoting macrophage calreticulin exposure (an “eat-me” signal), enhancing treatment efficiency. Leveraging cancer cell homotypic af­
and enhances tumor cell phagocytosis. The integration of MHT with finity [181], Daniele et al. [182] proposed the use of
immune evasion suppression offers a novel approach for anti-HCC regorafenib/IONP-loaded cell-derived lipid magnetic nanocarriers
therapy. Recent advances have extended beyond this paradigm. Ma (CDMNVs) coated with GBM membrane extracts, which demonstrated
et al. [166] engineered an AMF-manipulated tumor-homing bacterium potent antitumor activity. Liu et al. [78] designed gallic acid-coated
(AMF-Bac) with five functional modules: active navigation, signal magnetic nanorings (GA-MNCs) with clover-shaped magnetic cores
decoding, feedback, processing, and output. This system enables tumor and gallic acid shells for vascular targeting. The results indicate that
targeting, magnetothermal signal conversion, and thermally triggered intravesical administration of GA-MNCs upon AMF exposure inhibits
bacterial lysis to release anti-CD47 nanoantibodies (CD47nb), mini­ tumor progression through vascular disruption.
mizing systemic toxicity while boosting intratumoral CD47nb accumu­
lation for precision immunotherapy. Similarly, Jiang et al. [167] 4.1.4. Bone tumors
developed an AMF-controlled magnetogenetic platform. This system Bone tumors significantly reduce life expectancy and quality of life in
remotely activates tumor-infiltrating NK cells by regulating IL-2 young and middle-aged adults [183]. Curcumin, a natural compound,
expression through the HSP70 promoter. This approach enables shows promise in osteosarcoma treatment because it suppresses NF-κB
immunotherapy for deep-seated HCC. Furthermore, the combined and induces apoptosis [184]. Amin et al. [185] developed
application of MHT and chemotherapy shows comparable promise in Pluronic-coated SPIONs as thermoresponsive nanocarriers for curcumin
treating HCC. Li et al. [168] designed a magnetothermally responsive delivery, demonstrating synergistic cytotoxicity against osteosarcoma
nanocarrier/doxorubicin (MTRN/DOX) system using Mn-Zn ferrite NPs cells at 41 ◦ C in vitro (Fig. 6a). Crucially, treatments for bone tumors
(MZF-NPs). Unlike conventional Fe3O4 MNPs, MZF-MNPs provide su­ continue to target HSPs. Liang et al. [186] designed injectable PLGA gels
perior chemical stability, magnetic properties, biocompatibility, and coloaded with Fe3O4/MgCO3 nanoparticles and glucose oxidase
dual functionality as MRI contrast agents. In murine models, combining (Fe3O4/GOx/MgCO3@PLGA gel) to simultaneously target HSPs and
the heat released by magnetic targeting aggregation of MZF-NPs with promote bone regeneration, thereby enhancing MHT efficacy via ATP
DOX reduced the relative tumor volume by 75 % after 18 days, whereas depletion (Fig. 6b). Specifically, glucose oxidase first disrupts the
DOX or MNPs alone (without AMF) increased the tumor volume tricarboxylic acid cycle by decomposing glucose to generate hydrogen
sevenfold. These studies collectively demonstrate the promising poten­ peroxide, thereby suppressing ATP synthesis. When exposed to an
tial of combining MHT with chemotherapy as a synergistic treatment alternating magnetic field, the released Fe3+ ions and controlled thermal
strategy against HCC. conditions catalyze the decomposition of hydrogen peroxide into water
and oxygen, establishing a positive feedback loop that amplifies glucose
4.1.3. Brain tumors oxidase activity. Following osteosarcoma treatment, the gel filled the
Current treatments for glioblastoma multiforme (GBM) include sur­ bone defects and featured a porous architecture conducive to osteoblast
gical resection, chemotherapy, and radiotherapy. However, pronounced adhesion. Furthermore, sustained magnesium ion release endows the
intertumoral and intratumoral genetic heterogeneity [169], infiltrative scaffold with osteoinductive bioactivity, significantly enhancing osteo­
growth into healthy brain tissue [170], and the existence of cancer stem genic differentiation in vitro and bone regeneration in vivo. In animal
cells [171] contribute to poor prognosis. The blood‒brain tumor barrier models, magnetic nanocomposites have also demonstrated outstanding
(BBTB) further limits drug delivery [172]. Mild hyperthermia tumor elimination efficacy. Additionally, magnetic nanocomposites or
(42–45 ◦ C) induces cancer cell apoptosis without damaging normal Mg rods with excellent biocompatibility have also been successively
tissues [173], and MNP-based approaches have been used since 2008 applied in magnetic hyperthermia therapy, which demonstrated
(iron concentration: 112 mg/mL) [174]. However, the concentration of outstanding efficiency in bone tumors eradication. Zeng et al. [187]
nanoparticles is too high, and incomplete tumor eradication at these integrated Zn0.3Fe2.7O4 (ZFO) MNPs into PMMA bone cement,
temperatures, attributed to Hsp90 [175] and Hsp70 overexpression achieving 30 ◦ C heating under safe AC magnetic fields. In VX2

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Fig. 6. Schematic representation of magnetic nanomaterials to resist bone tumors. (a) Graphical abstract of the hybrid nanocarriers. Reproduced with
permission [185]. Copyright 2022, The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. (b) i) Synthesis of PLGA gels and the
encapsulation of glucose oxidase and Fe3O4/MgCO3 NPs. ii) Mild hyperthermia-triggered GOx release to induce starvation-magnetic synergistic therapy in 143B bone
tumors. Reproduced with permission [186]. Copyright 2023, The Authors.

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tumor-bearing rabbits, this magnetic cement inhibited tumor growth increased therapeutic efficacy, and deep tissue penetration capabilities
and improved survival rates. Liu et al. [188] introduced biodegradable [195]. Additionally, magnetic hyperthermia-based combination therapy
Mg rods that generate eddy currents under low-field AMF and then has advanced considerably in antimicrobial applications.
effectively ablated bone tumors in murine and rabbit models. This sig­
nifies the favorable biocompatibility of these nanocomposites and their 4.2.1. G+-targeted MHT platforms: bacterial entrapping, quorum sensing
significant potential for clinical translation. (QS) disruption, and targeted elimination
Overall, magnetic hyperthermia-based combination therapy has In cases of infected bone defects or IAIs, MHT combined with other
demonstrated significant efficacy against diverse malignancies, therapies can prevent infection progression by eliminating bacteria.
including breast cancer, hepatocellular carcinoma, glioblastoma multi­ However, large infected areas or implant surfaces may reduce the effi­
forme, and bone tumors, by strategically suppressing heat shock protein cacy of local therapy. Consequently, concentrating bacteria at infection
expression through three synergistic mechanisms: molecular inhibitors sites has become a critical strategy for enhancing antibacterial treat­
directly blocking HSP chaperone function, ATP depletion crippling ment. Recently, Zhao et al. [11] developed an intelligent
protein refolding capacity, and iron-mediated ferroptosis exacerbating trap-capture-kill antimicrobial system (MCPC/GM/HMFNs/drug com­
lipid peroxidation. Moreover, strategies enhancing tumor targeting posite) for treating infected bone defects. In this system, gelatin and
precision, delivering multimodal cytotoxicity, and reprogramming magnesium oxide (GM) nanoparticles in magnesium calcium phosphate
tumor microenvironments have been successfully implemented. Future bone cement (MCPC) act as trapping agents to concentrate bacteria.
advancements require AI-optimized platforms to control tumor hetero­ Through synergistic MHT mediated by superparamagnetic hollow
geneity, closed-loop magnetic navigation systems for real-time thera­ mesoporous ferrite nanoparticles (HMFNs) with high drug-loading ca­
peutic modulation, standardized nanomanufacturing protocols, pacity, ROS damage from nanomagnesium oxide (MgO), adsorptive
increased efficiency of targeted drug delivery, and clinical practice [189, disruption, sustained drug release, and bacterial membrane integrity
190]. Such innovations will establish precision oncology frameworks and permeability are compromised. This intelligent system ultimately
capable of eradicating treatment-resistant deep-tissue malignancies resulted in the effective inactivation of S. aureus. (Fig. 7a). QS facilitates
through more comprehensive strategies. chemical communication among bacteria [196]. Under high bacterial
A partial summary of antitumor-associated magnetic nanomaterials density conditions, bacteria use QS to coordinate behaviors such as the
is shown in Table 3, which shows the types of cancer these magnetic production of exopolysaccharides (EPSs) and mature biofilm formation.
nanomaterials can be used for, their functions, and their dominance. Thus, disrupting QS to inhibit biofilm development is a promising
strategy. Inspired by this phenomenon, Luo et al. [197] designed a
synergistic therapeutic approach combining QS interference-assisted
4.2. Antibacterial action therapy (QSIAT) and immunomodulation using hyaluronic acid-coated
ferrite (HA@MnFe2O4). In this system, HA@MnFe2O4 disintegrates at
Infected bone defects caused by high-energy trauma or open frac­ infection sites, releasing MnFe2O4 nanoparticles that penetrate biofilms,
tures [191] and implant-associated infections (IAIs) [192] are common downregulate QS-related genes (agrA, agrC, hld), and are subsequently
complications of surgical procedures. The repair and reconstruction of eliminated via magnetic heating. Additionally, disaccharides produced
the infected microenvironment is more challenging because of insuffi­ by hyaluronidase-digested HA (e.g., from Group B streptococci and
cient blood or oxygen supply at the infected site and bacterial biofilm other gram-positive bacteria) promote wound healing and reduce
formation on implant surfaces or surrounding tissues [193]. These inflammation (Fig. 7b). This combined strategy, which integrates
conditions pose significant threats to human health and impose a sub­ anti-inflammatory effects, QS suppression, magneto-thermal biofilm
stantial economic burden on society. Furthermore, the concurrent rise in disruption, and immunomodulation, offers novel insights for future
antibiotic resistance rates and decline in novel antibiotic development MHT-based antimicrobial therapies.
have reestablished infections associated with drug-resistant pathogens Additionally, while MNPs have been widely employed for bacterial
as major global public health concerns [194]. Consequently, strategies detection and infection control [198], precise bacterial targeting re­
to address widespread bacterial infections and antimicrobial resistance mains challenging [199]. Bacteria utilize D-amino acids for the
are increasingly urgent. Recently, MHT has gained attention as a biosynthesis of peptidoglycan cell walls, whereas mammalian cells
promising antiinfective strategy owing to its noninvasive nature,

Table 3
Antitumor-associated magnetic nanomaterials.
Cancer Material Function Dominance Ref.

Breast cancer FA-Gel/FeNP Eliminate breast cancer cells. Combination of magnetic hyperthermia therapy and [155]
chemotherapy,
promote adipose tissue rebuilding.
Hepatocellular CD44-HSPI/Fe3O4@SiNPs Suppress tumor growth in breast cancer stem cells. Inhibit the promotion of cancer stem cells by reducing [158]
carcinoma AIPH@MAH Implement breast-conserving therapy to overcome HSP90. [160]
Brain cancer MNPs@PEI-FA/pDNA tumor hypoxia. Combination of magnetic hyperthermia therapy and [167]
Bone cancer MTRN/DOX Tumor suppression. oxygen-irrelevant free-radical enhances cytotoxicity. [168]
Lipid magnetic Thermo-chemotherapy synergizes to kill HCC cells. Utilize the nonspecific killing properties of NK cells, [182]
nanocarriers Promote glioblastoma multiforme cells death. unlimited depth of penetration. [78]
Gallic acid-coated magnetic Effectively kill glioblastoma multiforme cells. Cause temporal-spatial synchronism of thermo- [186]
nanoclovers Kill bone tumor cells and promote the regeneration chemotherapy. [188]
Fe3O4/GOx/ of bone defects caused by bone tumors. Enhance selectivity of nanocarriers for glioblastoma
MgCO3@PLGA gel Perform magnetic thermal ablation. multiforme,
Bio-degradable MgA rods elevate the ability of drugs to penetrate the blood-brain
tumor barrier.
Efficient vessel targeting,
enhance drug delivery through targeted vascular disruption.
Inhibit ATP production to reduce HSP expression for
synergistic osteosarcoma.
Nonmagnetic degradable MgA rods kill large-size bone
tumors and show excellent biocompatibility.

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Fig. 7. Schematic representation of systematic schemes for magnetic nanomaterials to resist bacteria. (a) Schematic illustration of the synthesis of MCPC/
GM/HMFNs/Drug composites. Reproduce with permission [11]. Copyright 2023, Wiley-VCH GmbH. (b) Schematic of the preparation of hyaluronic acid-coated
ferrite NPs (HA@MnFe2O4) and its multiple synergistic therapeutic strategy. Reproduce with permission [197]. Copyright 2023, Wiley-VCH GmbH. (c) Sche­
matic illustration of metabolic labeling mediated targeting of bacteria. First, d-Lys derivatives with TCO groups were first metabolically incorporated into the
peptidoglycan cell wall. Subsequently, clickable Janus MNPs (Tz groups introduced by reaction of Tz-NHS with NH2-PEG-SH functionalized Au/MFO) were con­
jugated to the TCO groups. The MFO component of the nanoparticle exhibits multifunctionalities, including peroxidase activity, magnetic separation, and magnetic
heating, which can be used to detect and kill bacteria. Reproduce with permission [202]. Copyright 2020, Wiley-VCH GmbH. (d) Schematic diagram of the three
main resistant barriers in MDR E. coli and the mechanisms of overcoming AbR by MWH. Reproduce with permission [206]. Copyright 2022, Wiley-VCH GmbH.

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exclusively use L-amino acids. This distinction enables targeted bacterial such as pifithrin-μ (PES) can be introduced to enhance bactericidal ef­
interventions using D-amino acids [200]. Strategies employing D-amino ficacy. To improve PES selectivity, Peng et al. [216] engineered
acids in complex biological environments have further demonstrated ZIF-8-coated mesoporous polydopamine (MPDA) core-shell nano­
their specificity for bacterial targeting [201]. On this basis, Hou et al. particles. These nanoparticles remain stable under physiological con­
[202] reported a bacterial targeting system based on Au/MnFe2O4 ditions but degrade in the acidic environment of bacterial infections,
(Au/MFO) Janus MNPs. In this system, D-Lys-PEG-TCO was integrated release zinc ions and encapsulate PES. The results demonstrated that the
into the peptidoglycan cell walls of gram-positive bacteria in a metabolic MPDA nanoparticles exhibited sensitive pH-responsive release capabil­
way. This material features Au/MFO Janus MNPs with tetrazine (Tz) ities and effectively eliminated bacteria and biofilms. This study offers
functionalization. These nanoparticles bind to trans-cyclooctene (TCO) insights for MHT or combination therapy strategies that combine MHT
on bacterial cell walls via Tz-TCO click reactions. The peroxidase ac­ and PTT to counteract bacterial thermotolerance in hyperthermia
tivity of the MFO component quantifies bacteria through therapies. Similarly, gram-negative bacteria can form biofilms that resist
nanozyme-based chromogenic detection. Finally, magnetic separation invasion by external agents such as antibiotics. Recently, the magneto­
enriches bacteria, followed by magnetothermal eradication (Fig. 7c). tactic bacteria Magnetococcus maritimus (MC-1) has been used to power
Inorganic MNPs typically exhibit an isoelectric point (IEP) near 7 at biohybrid systems for tumor targeting in mice, suggesting that their
physiological pH, necessitating polymer coatings for functionalization clinical potential remains to be further investigated [217]. These bac­
[203]. However, these coatings may obscure their suboptimal magnetic teria swim via a rotating bipolar flagellum and contain endogenous
properties and limit their practical application [204]. To address this magnetic vesicle nanoparticles. Owing to their ability to sense their
limitation, Y. Jabalera et al. [205] utilized MamC, a Magnetococcus environment, they can be externally guided under low magnetic fields.
maritimus MC-1 magnetosome-associated protein, to synthesize bio­ Fluid propulsion enables targeted drug delivery to deeper biofilm re­
mimetic magnetic nanoparticles (BMNPs). They designed a nano­ gions [218]. Morgan et al. [219] integrated the magnetotactic bacteria
formulation combining AS-48-functionalized BMNPs with MHT. Under Magnetosopirrillum gryphiswalense (MSR-1) into mesoporous silica
an AMF, BMNPs generate localized hyperthermia (41–45 ◦ C) to trigger microtubules preloaded with ciprofloxacin (CFX). This microtubule
drug release. AS-48, a 70-residue cyclic peptide from Enterococcus fae­ eradicates biofilms and kills bacteria by magnetically targeting bacterial
calis, acts against gram-positive bacteria and pathogens but shows biofilms and penetrating deep layers to release CFX. Furthermore, Yue
limited efficacy against gram-negative species because of their outer et al. [220] fabricated organic-inorganic nanoflowers (MN-Cu × NFs)
membrane barrier. Thus, integrating MHT with targeted therapies en­ via bacterial biofilms on magnetic vesicles (organic components) and
hances synergistic antimicrobial outcomes. copper(II) ions (inorganic components) and then anchored low-cost
AgNPs (Ag/MN-Cu × NFs) with broad-spectrum antimicrobial activity
4.2.2. G− -targeted MHT platforms: outer membrane permeabilization, onto the nanoflowers. This system promoted the healing of
multidrug-resistance reduction, and biofilm disruption infection-induced wounds. These findings indicate that combination
Unlike gram-positive bacteria, gram-negative bacteria (e.g., E. coli) therapy integrating MHT has achieved significant efficacy in combating
possess peptidoglycan or other cell wall components and are further bacterial infections.
protected by a unique outer membrane (OM) structure. OM consists of In conclusion, united antimicrobial platforms rooted in magnetic
an asymmetric lipid bilayer, phospholipids in the inner leaflet and li­ hyperthermia therapy exhibit remarkable therapeutic versatility, effec­
popolysaccharides (LPS) in the outer leaflet, forming a permeability tively combating gram-positive bacteria through magnetic capture,
barrier against most antibiotics [207]. The β-barrel assembly machine quorum-sensing disruption, and targeted clearance, while concurrently
(BAM complex), which is critical for OM biogenesis, facilitates the addressing the multidrug resistance of gram-negative bacteria via outer
transport, insertion, and folding of outer membrane proteins (OMPs) membrane permeabilization, efflux pump inhibition, and advanced
[208]. The central component of the BAM complex, BamA, is an OMP biofilm eradication. These synergistic strategies overcome traditional
exposed on the OM surface. It increases bacterial susceptibility to antibiotic limitations by physically disrupting bacterial defenses and
environmental stress [209]. Moreover, multidrug-resistant E. coli em­ enhancing biofilm penetration. In the near future, the rise of more
ploys other defense mechanisms involving efflux pumps and enzymatic emerging technologies, particularly artificial intelligence, may signifi­
antibiotic degradation/modification. Mao et al. [206] developed an cantly reinvigorate the antibacterial applications of magnetic hyper­
innovative in situ microwave hyperthermia (MWH) strategy using poly thermia therapy.
(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with con­ A partial summary of antibacteria-associated magnetic nano­
ventional antibiotics. The Segmental motion of PLGA polymers converts materials is shown in Table 4, which shows the bacteria killed by these
mechanical energy to heat. Under MWH, conventional antibiotics magnetic nanomaterials, their functions, and their dominance.
overcome these defenses by increasing BAM complex-mediated OM
permeability, downregulating MDR efflux pump proteins, and impairing 4.3. Immunomodulation
the synthesis/activitity of enzymes (Fig. 7d). This approach suggests
that analogous benefits could arise from substituting the MWH with the In recent decades, cancer immunotherapy has emerged as a prom­
MHT. Metal-organic frameworks (MOFs) are porous coordination ising approach for treating cancer because it extends beyond primary
polymers that serve as templates for synthesizing magnetic iron oxi­ tumor inhibition to prevent metastasis or recurrence by harnessing the
de/carbon composites via pyrolysis [210]. The defined pore structures patient’s innate or adaptive immune system [221]. However, the low
and binding sites enable the spatial confinement of doped NPs. These immunogenicity of most tumors often hinders immune activation [222].
features make MOFs ideal carriers for IONPs [211,212]. Chung et al. For example, studies have shown that immunosuppressive macrophages
[213] utilized MOF-derived Fe3O4@C encapsulated in PLGA micro­ and dendritic cells (DCs) in the bladder tumor microenvironment pro­
spheres to create magnetically responsive NO-releasing materials mote tumor progression through complex mechanisms [223]. Thus,
(MagNORM). Leveraging NO’s antibacterial activity at >1 μM concen­ reprogramming the tumor immune microenvironment from an immu­
trations, the dual-phase NO release of MagNORM (burst and steady) nosuppressive state to an immune-activated state is critical for effective
targets bacterial infections and effectively kills bacteria. Like MHT, treatment. MHT, which utilizes specific MNPs, has demonstrated effi­
photothermal therapy (PTT) is a viable alternative for combating bac­ cacy in activating immune responses, and potentially inhibits tumor
terial biofilm infections [214]. However, bacteria can develop acquired metastasis and recurrence [195,224]. Various magnetic
thermotolerance by upregulating HSPs to enhance their vitality and hyperthermia-based combination therapies targeting the immunosup­
resistance to thermal damage, thereby impairing PTT efficacy and pressive TME, and the efficacy or progress achieved in recent years are
resulting in a poor prognosis [215]. To overcome this, HSP inhibitors reviewed here.

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Table 4 both components under an AMF induced liquid-gas phase transition in

Antibacteria-associated magnetic nanomaterials. RPPs and generated microbubbles. This process delivered three simul­
Bacteria Material Function Dominance Ref. taneous outcomes: the cavitation effect of microbubbles strengthened
local effects of MHT, phase transition accelerated R848 release from
G -Targeted
+

MHT PLGA, and microbubbles acted as ultrasound contrast agents for

platforms real-time imaging. Notably, R848 activates antigen-presenting cells
Streptococci HA@MnFe2O4 Kill bacteria Reduce QS- [197]
(APCs, e.g., dendritic cells), and cavitation effects disintegrate cell
G. aureus MCPC/GM/ and promote related gene [11] membranes to increase liberation and presentation of DAMPs. This
G− - HMFNs/Drug tissue expression and [202] process converts immunologically inert ("cold") tumors to reactive
Targeted composite regeneration. attenuate biofilm [205] ("hot") states, alters the immunosuppressive tumor microenvironment,
MHT Au/MnFe2O4 Kill bacteria stress response. [206]
and heightens tumor sensitivity to immunotherapy agents (Fig. 8a).
platforms Janus NPs and inhibit Simultaneous [220]
E. coil AS-48- biofilm trapping, [213] Moreover, MNPs can promote macrophage polarization from the pro­
functionalized formation. capturing and [219] tumor M2 phenotype to the antitumor M1 phenotype, activating innate
biomimetic Eliminate killing functions. immune responses against tumors [229]. Min et al. [230] conceived a
magnetic bacterial Realize targeted mild magnetothermal modulation theranostic modality grounded in the
nanoparticles infections. killing of
(BMNPs) Achieve local bacteria through
nanocatlytic nanoplatform ZCMF@PEG-AF (ZCMF-AF). They function­
Antibiotics- antimicrobial metabolic alized ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (ZCMF) with
loaded PLGA/ therapy. labeling of anti-F4/80 antibodies (AF). Under AMF-mediated hyperthermia
microparticles. Effectively kill bacteria with d- (41–42 ◦ C), ZCMF-AF triggered the catalytic generation of hydroxyl
Ag/MN-Cu × multidrug- amino acids.
radicals through the release of iron ions in acidic cellular environments.
NFs resistant E. coli. Reduce the
MagNORM Synergistic development of This reprogrammed TAMs from the immunosuppressive M2 phenotype
MSR-1/ damage to multi-drug to antitumor M1 phenotype. Crucially, reactivated M1 macrophages
mesoporous E. coli and G. resistance, combined with magnetothermal tumor damage propagated an immune
silica aureus. attain broad- cascade that matured dendritic cells and subsequently mobilized cyto­
microtubules Magnetically spectrum
preloaded with trigger localized
toxic T lymphocytes against tumor cells. In addition to their ability to
CFX sterilization antimicrobial interact with macrophages, MNPs also enhance inflammation by
and promote action. recruiting macrophages and activating Toll-like receptor pathways to
wound healing. Restoration of induce proinflammatory responses [231]. Innate immunity also relies on
Exhaustive multidrug-
NK cells, which exert cytotoxic effects. Studies have demonstrate [232]
removal of resistant E coli
bacterial susceptibility to that NK cells express activating/inhibitory receptors that regulate tumor
biofilm. conventional cell killing. Major histocompatibility complex (MHC) class I molecules,
antibiotics by which are targeted by T cells, also act as inhibitory ligands for NK cells.
various Tumor cells often downregulate MHC class I to evade T cells, inadver­
mechanisms.
Promote wound
tently activating NK cell recognition. MHT upregulates NKG2D re­
healing in the ceptors on NK cells and their ligand MHC I-like chain-associated protein
face of bacterial A (MICA) on tumors [233], thereby enhancing nonspecific killing of
infection cells.
without causing
toxicity to major
organs. 4.3.2. Innate/adaptive immune response
Innovatively MHT activates the host’s innate immune response, and the resulting
utilize the broad- adaptive immunity enhances its therapeutic efficacy. Shi et al. [12]
spectrum proposed a strategy in which hyaluronic acid (HA)-modified MNPs
antibacterial
activate both immune pathways. First, rapid innate immunity is trig­
activity of NO.
Targeted gered via the polarization of tumor-associated macrophages to the
delivery of antitumor M1 phenotype through the TLR4/MyD88/NF-κB p65
antibiotics to pathway. Second, a sustained adaptive response is activated by con­
biofilm sites
verting T cells into cytotoxic T-cells. This occurs as mild MHT releases
utilizing MSR-1.
tumor-associated antigens, which are internalized by DCs, leading to DC
maturation and antigen presentation. Tumor-associated antigens
4.3.1. Innate/inherent immune response generated during MHT, such as HSPs, trigger antitumor immunity
In recent years, MHT-induced immunomodulation has gained [228]. Intracellular HSPs protect tumor cells from thermal stress,
increasing attention. However, single mild MHT faces limitations whereas extracellular HSPs facilitate antigen delivery to
including prolonged treatment time, repeated procedures, limited tumor antigen-presenting cells via MHC molecules [234]. For example,
suppression, and insufficient antigen exposure [225]. Recent research HSP-peptide complexes internalized by APCs activate CD8+ T cells and
highlights the anticancer synergy of microbubbles. Studies have shown CD4+ T-helper cells via MHC-I/II pathways [235]. Intracellular
that heated microbubbles rapidly expand and explode to generate HSP-mediated thermoresistance during magnetic hyperthermia cancer
microcavitation effects. This produces localized mechanical damage in therapy (MHCT) compromises therapeutic efficacy at tumor sites. This
surrounding cells or tissues. This phenomenon has proven effective for persistent limitation presents significant clinical challenges for localized
tumor destruction in combination therapies [226,227]. Thus, combining thermal treatments. According to previous studies, HSP90 inhibition
MHT with microbubbles may enhance anticancer efficacy. Qin et al. enhances MHC-I expression on tumor cells, recruiting T cells for stronger
[228] developed a composite system that combines superparamagnetic immune responses [236]. Additionally, Huang et al. [237] reported that
iron oxide nanoparticles (SPIOs) with R848-PFP@PLGA nanodroplets HSP90 inhibition synergized with subablative hyperthermia by
(RPPs). They prepared RPPs via w/o/w double emulsification to increasing calreticulin exposure and downregulating CD47, thereby
encapsulate the low-boiling-point (29 ◦ C) phase-change agent PFP and inducing immunogenic forms of cell death in colon cancer cells. Sharma
the immunoadjuvant R848 within PLGA shells. Intratumoral injection of et al. [238] proposed a combination therapy strategy integrating mag­
netic hyperthermia therapy with the HSP90 inhibitor 17-DMAG

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Fig. 8. Schematic representation of series of protocols for immunomodulation by magnetic nanomaterials. (a) Schematic of the fabrication of SPIO + RPPs
and the mechanism by which RPPs potentiate mild MHT against tumor proliferation and metastasis. i) Illustration of the synthesis of SPIO + RPPs and the process of
MDV. ii) The proposed mechanism of mild MHT potentiated by RPPs to prevent tumor proliferation and metastasis. Reproduced with permission [228]. Copyright
2023, The Authors. (b) Schematic representation of a combinatorial strategy using 17-DMAG as an inhibitor of HSP90 following MHCT. Reproduced with permission
[238]. Copyright 2024, American Chemical Society. (c) Schematic representation of the experimental protocol. Reproduced with permission [238]. Copyright 2024,
American Chemical Society. (d) and (e) show the time course of tumor volume in each group. The tumor volume increased over a 36-day period in all control groups.
However, in the NPs-MHCT and NPs-MHCT-17-DMAG groups, we observed a reduction of 44 and 65 %, respectively, in the tumor volume of 1◦ T within 8 days
post-MHCT_1 compared to the control PBS group. The group subjected to combinatorial therapy showed complete regression of the 1◦ T tumor within 20 days
post-MHCT_2. Moreover, 2◦ T tumor growth was significantly reduced by 42 % and 53 % in the MHCT alone and combinatorial therapy groups, respectively, within 8
days of MHCT_1. We also observed a significant difference of 14 % in the tumor growth inhibition rate of 1◦ T between the combinatorial therapy-treated group and
the MHCT alone group within 8 days, validating the critical role of HSP90 in cancer survival. Reproduced with permission [238]. Copyright 2024, American
Chemical Society.

(Fig. 8b), which resulted in 65 % and 53 % tumor inhibition at the immunosuppressive function of tumor-associated macrophages. This
primary and secondary sites respectively (Fig. 8c–e). Notably, their dual-pronged attack, which leverages innate cytotoxicity while
analysis of the expression of multiple genes, including interleukins, reversing T-cell exhaustion, creates a self-sustaining immunological
TNF-α, IFN-γ, caspase-3, Akt, and calreticulin (CRT), revealed that this cycle in which liberated tumor antigens fuel durable adaptive responses.
combination therapy rapidly eliminates glioma cells while concurrently Advanced technologies will empower magnetic nanocomposite plat­
suppressing distant metastasis to sites such as lungs. The precise un­ forms to establish spatiotemporal control over immune synapses while
derlying mechanism remains elusive, although it potentially involves enabling real-time functional monitoring through sophisticated means.
the death of tumor cell-released extracellular HSPs, which activate This evolution may transform hyperthermia into systemic immuno­
innate and adaptive immune responses. HSP70 also modulates immu­ therapy capable of eradicating metastatic disease and establishing life­
nity by enhancing antigen presentation via MHC-II and upregulating long antitumor surveillance.
costimulatory markers (CD86, CD83, and CD40) on DCs, which activate A partial summary of immunomodulation-associated magnetic
CD8+ T cells for adaptive antitumor responses [239]. nanomaterials is shown in Table 5, which shows the immune cells that
Since the discovery of programmed death-ligand 1 (PD-L1) being these magnetic nanomaterials can act on, their functions, and their
selectively expressed across numerous tumor types, checkpoint blockade dominance.
via α-PD-L1 antibodies combined with magnetic hyperthermia therapy
has minimized clinical immune-related adverse events [240]. In BALB/c
4.4. Tissue regeneration
mice bearing bilateral 4T1 breast tumors, Shi et al. [224] administered
α-PD-L1 checkpoint inhibitors with CoFe2O4@MnFe2O4
Bone exhibits remarkable self-repair and regenerative capacity, and
nanoparticle-based magnetic hyperthermia therapy. This dual regimen
its formation and function are gradually restored after partial loss or
eliminated primary tumors while suppressing secondary growth at
defects [246]. However, bone damage exceeding critical thresholds,
distant sites. Furthermore, macrophage colony-stimulating factor 1
typically >2 cm in length or >50 % volume loss, often leads to
(CSF1) significantly promotes immunosuppression. The CSF1/CSF1R
nonunion, malunion, or pathological fractures [247]. Tumor-induced
signaling pathway regulates monocyte differentiation while sustaining
bone defects, such as those caused by osteosarcoma, require dual stra­
the immunosuppressive and tumor-promoting functions of
tegies: promoting regeneration while preventing tumor recurrence
tumor-associated macrophages [241]. Thus, CSF1/CSF1R blockade with
[248]. Magnetic hyperthermia therapy enhances tissue regeneration
inhibitors represents a promising anticancer immunotherapy strategy.
through synergistic mechanisms: thermal-mediated cellular modulation
Fang et al. [242] developed a combination therapy that merged the
(boosting osteogenic differentiation) and magnetoresponsive spatio­
CSF1R inhibitor BLZ945 with magnetic hyperthermia therapy to
temporal control of bioactive factor release. In tissue engineering, mild
reprogram the tumor immune microenvironment. This synergistic
hyperthermia (38–42 ◦ C) balances therapeutic efficacy with safety,
MHT-immunotherapy approach suppresses tumor growth and recur­
avoiding damage to healthy tissue [13]. Magnetic nanoparticles further
rence. They engineered magnetic liposomes modified with
enable the modulation of cellular function under external magnetic
cell-penetrating peptides for magnetically targeted BLZ945 delivery and
fields because of their bioactivity and surface-coupling capabilities
enhanced intratumoral penetration. In colon cancer models, this thera­
[249].
peutic system effectively suppressed tumor growth while concurrently
establishing long-term immunological memory to prevent recurrence.
4.4.1. Bone regeneration
Additionally, studies have shown that regulatory T cells (Treg cells),
As the essential initial phase of tissue healing, inflammation criti­
which express CD4, CD25, and forkhead box protein P3 (FOXP3), can
cally restores tissue homeostasis postinjury or infection [250]. When
negatively regulate innate and acquired immune responses by inhibiting
activated, this response mobilizes immune defenses against harmful
immune cell proliferation [243]. Treg cells normally constitute 5 %–10
agents while launching subsequent tissue regeneration [251]. During
% of CD4+ T cells, but can constitute as many as 20 %–30 % of the tumor
tissue healing, the phenotypic switch of macrophages from the proin­
microenvironment. This leads to a poor prognosis in patients with a
flammatory (M1) subtype to the antiinflammatory (M2) subtype is
variety of tumors [244]. Magnetic hyperthermia therapy has been
dynamically regulated [252]. M1 macrophages dominate early inflam­
proven to reduce Treg cell levels in the tumor microenvironment and
mation, and secrete TNF-α and ROS to clear necrotic tissue, however,
enhance immune-mediated tumor killing [245].
excessive activation may cause microenvironment deterioration and
In summary, magnetic hyperthermia therapy-driven immunomodu­
inhibit tissue repair. Conversely, M2 macrophages produce
latory strategies orchestrate comprehensive antitumor immunity by
anti-inflammatory cytokines such as TGF-β and IL-10 to facilitate tissue
simultaneously activating innate defenses and dismantling adaptive
remodeling and fibrosis [253]. Thus, driving the M1-to-M2 transition
immunosuppression. These platforms thermally reprogram macrophage
represents a refined strategy for accelerating bone regeneration. Cheng
polarization toward antitumor phenotypes or synergize with micro­
et al. [254] conjugated amino-terminated superparamagnetic nano­
bubble cavitation to rupture immunologically "cold" tumor barriers.
particles (SPMNPs) to collagen fibers via genipin crosslinking to fabri­
These platforms also enhance NK cell-mediated tumor lysis. Crucially,
cate superparamagnetic nanocomposite hydrogels (Fig. 9a). More
they concurrently ablate adaptive immune suppression through PD-L1
importantly, magnetic field (MF) intervention temporally controlled
checkpoint blockade and disrupt the CSF1/CSF1R-mediated
macrophage polarization from the M1 phenotype to the M2 phenotype.

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Table 5
Immunomodulation-associated magnetic nanomaterials.
Type/Immune cells Material Function Dominance Ref.

Innate immunity

Dendritic cells SPIOs/RPPs Activate innate defenses to inhibit Utilize a triple strategy of combined magnetic hyperthermia [228]
Macrophage ZCMF@PEG-AF (ZCMF-AF) tumor proliferation and metastasis. therapy, microbubble cavitation, and chemotherapy. [230]
NK cells Related magnetic nanocomposite Mobilize M1 macrophages to kill Activation of M1 macrophages combined with magnetic [232]
Innate/adaptive Fe3O4 NPs/17-DMAG tumor cells. hyperthermia therapy causes damage and propagates an [238]
immunity α-PD-L1 checkpoint inhibitors/ Kill tumor cells nonspecifically. immune cascade reaction. [224]
T cells CoFe2O4@MnFe2O4 nanoparticle. Block tumor growth and distant Upregulation of NKG2D receptors on NK cells and MICA on [242]
Treg cells BLZ945/Magnetic liposomes modified metastasis. tumors by magnetic hyperthermia therapy enhance nonspecific [244,
with cell-penetrating peptides. Eliminate primary tumors while killing capacity. 245]
Magnetic hyperthermia therapy suppress secondary growth at distant Cooperate with the HSP90 blockade to further activate immune
sites. systems of host.
Suppress tumor growth and Combine magnetic hyperthermia therapy with checkpoint
recurrence. blockade immunotherapy.
Enhance the tumor-killing effect of Reprogram the tumor immune microenvironment and establish
immune cells. long-term immunological memory to prevent recurrence.
Magnetic hyperthermia therapy reduces Treg cell levels in
tumor microenvironment and declines its blockage of immune
cells function.

This MF-regulated mechanism ensures adequate early-phase M1 expression, activating the phosphatidylinositol 3-kinase/protein knase B
macrophage infiltration after injury while accelerating their later-stage pathway (PI3K/Akt) pathway and upregulating hypoxia-inducible
transition to the M2 phenotype. This strategy preventes dysregulated M1 factor-1α (HIF-1α), promoting osteoblast mineralization and angiogen­
activation yet preserves essential physiological inflammation to initiate esis respectively. Enhanced angiogenesis further stimulates bone
tissue repair processes. regeneration. Leveraging this mechanism, researchers have designed
Moreover, advanced engineering technologies and multifunctional core–shell structured MIONs (CoFe2O4@MnFe2O4), functionalized with
materials significantly enhance bone tissue regeneration. Additive the osteoinductive peptide Arg-Gly-Asp (RGD) via ligand exchange.
manufacturing (AM) and 3D printing have advanced biomedical engi­ These MION-RGD complexes were encapsulated in an agarose
neering, particularly in bone regeneration and oncology [255]. Sodium (MION-RGD/agarose, MRA) hydrogel, synergistically driving bone
alginate (SA), a biocompatible hydrogel with extracellular matrix-like regeneration and angiogenesis through the described pathways.
properties, is widely used for 3D bioprinting [256]. Shamoon et al.
[257] enhanced SA-based hydrogels by doping them with polyvinyl 4.4.2. Others
alcohol (PVA) and nanohydroxyapatite (HA), improving their viscosity, In addition to bone regeneration, magnetic hyperthermia therapy
osteoinductivity, and osteoconductivity. They further integrated mag­ synergizes with other therapies to facilitate tissue repair. Magnetic-
netic graphene oxide (MGO) into PVA/SA/HA scaffolds for posttumor based Joule hyperthermia therapy (MJHT) locally elevates the temper­
bone regeneration. In addition, Borges et al. [258] incorporated pristine ature of the targeted tissue to 43–46 ◦ C. This controlled hyperthermia
SPIONs into HA/chitosan (CS)/PVA scaffolds (Fig. 9b). An in vitro study induces physiological dysfunction in abnormal cells, culminating in
using human osteosarcoma Saos-2 cells revealed that, compared with apoptotic or necrotic death [28]. Na et al. [263] engineered a spatio­
the CS/PVA/HA scaffold, the inclusion of pSPION significantly temporal therapeutic platform termed Joule-Assisted Nanotherapeutic
enhanced cellular adhesion, proliferation, and alkaline phosphatase Urethral Stent (JANUS) to treat urethral strictures while regenerating
(ALP) expression, promoting bone regeneration. Furthermore, a multi­ the urothelium. The system integrates a biodegradable magnesium alloy
functional platform was fabricated by integrating ferromagnetic Fe3S4 stent coated with thermally responsive polycaprolactone (TRP) and
microflowers onto 3D-printed bioactive akermanite (AKT) scaffolds via sirolimus nanoparticles (nSRL) on opposite sides. This dual-sided
a hydrothermal process [259] (Fig. 9c). Ferrimagnetic Fe3S4 increased coating enables distinct functions: magnetically triggered Joule heat­
ROS via magnetothermal effects for tumor killing, whereas ing from the stent initiates local hyperthermia, simultaneously releasing
scaffold-released Mg2+, Si2+, and Ca2+ ions promoted regeneration. nSRL from the TRP matrix to enhance bacterial ablation and suppress
Additionally, research on the mechanisms that enhance bone smooth muscle proliferation. Concurrently, the stent releases Mg2+ ions
regeneration has achieved groundbreaking advances. By employing that promote endothelial regeneration. JANUS demonstrates significant
these well-established biological principles, investigators can strategi­ potential as a balanced therapeutic platform for treating urethral stric­
cally engineer advanced magnetothermal platforms to optimize bone tures through integrated ablation and tissue regeneration. Moreover,
repair. These integrated systems capitalize on precisely calibrated integrating hyperthermia with chemotherapy unlocks future opportu­
thermal control modules and responsive nanocarriers to coordinate nities to engineer multifunctional regenerative systems anchored in
three critical regenerative processes: synchronized immunomodulation, magnetic hyperthermia therapy. Studies have also highlighted the po­
functional vascularization, and targeted osteogenesis [260,261]. Such tential of MHT in nerve repair via magnetothermal-neurostimulation
multifunctional MHT architectures thereby pioneer transformative interplay [13]. For example, under magnetic fields, MNPs non­
pathways for structural and functional bone restoration in complex invasively activate thermosensitive TRPV1 receptors, triggering
defect environments. Jia et al. [262] conducted an in-depth study on the reversible neuronal activation [264]. Similarly, SPIONs generate local­
mechanism by which magnetic iron oxide nanoparticles (MIONs) induce ized heat (>42 ◦ C), opening TRPV1 channels to induce calcium influx
the osteogenic differentiation of mesenchymal stem cells (MSCs) on the and neuronal action potentials without toxicity [265]. For cartilage
basis of prior research (Fig. 9d). They confirmed that this phenomenon is repair, Pavel et al. [266] developed thermoresponsive liposomes
linked to activation of the mitogen-activated protein kinase (MAPK) encapsulating spider silk coated with ferromagnetic Mn0.9Zn0.1Fe2O4
pathway and upregulation of the long noncoding RNA INZEB2. As key nanoparticles. When exposed to an alternating magnetic field, ferro­
angiogenic factors in bone defect repair, MIONs release iron and cobalt magnetic nanoparticles generate heat that ruptures thermoresponsive
ions during degradation, accelerating neovascularization and improving liposomes, releasing spider silk precisely at damaged cartilage sites. The
the blood supply. Furthermore, AMF-induced heat stress elevates HSP90 silk provides exceptional mechanical support while creating a

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Fig. 9. Schematic representation of series of protocols for regenerating tissue with magnetic nanomaterials. (a)Schematic illustration of magnetized
nanocomposite hydrogels for on-demand immunomodulation via temporally controlled macrophage phenotypic transition in response to a magnetic field. Fabri­
cation processes for the magnetized hydrogels and the scheduled inflammation regulation strategy through timely programmed macrophage phenotypic switching
from M1 to M2 polarization under the manipulation of a magnetic field. M1/M2, M1/M2 polarized macrophage; BMSC, bone mesenchymal stem cell. Reproduced
with permission [254]. Copyright 2022, The Authors. Small published by Wiley -VCH GmbH. (b) 3D printed scaffolds after freeze-drying: a) P1_B (CS/PVA/HA), b)
P1_pS1 (CS/PVA/HA/15 %pSPIONs), c) P1_pS3 (CS/PVA/HA/30 %pSPIONs), and d) P1_pS5 (CS/PVA/HA/45 %pSPIONs); SEM images displaying the morphology
and shape of the filaments obtained for the 3D printed scaffolds: e) P1_B, f) P1_pS1, g) P1_pS3, and h) P1_pS5. SEM images scale bar: 500 μm. Reproduced with
permission [258]. Copyright 2023, The Authors. (c) Photographs and surface morphology of 3D-printed bioceramic scaffolds before and after hydrothermal process.
a) Photographs of scaffolds treated under different temperature and precursor concentration. SEM images of pure AKT scaffolds ((b1), (b2), (b3)), 0.02 M micro­
lamella Fe3S4-modified AKT scaffolds ((c1), (c2), (c3)), 0.04 M microlamella Fe3S4-modified AKT scaffolds ((d1), (d2), (d3)), 0.02 M microflower Fe3S4-modified
AKT scaffolds ((e1), (e2), (e3)) and 0.04 M microflower Fe3S4-modified AKT scaffolds ((f1), (f2), (f3)), respectively. After hydrothermal reaction, Fe3S4 with
different morphology grew on the surface of the AKT scaffolds. Reproduced with permission [259]. Copyright 2021, The Authors. (d) Schematic diagram of the
mechanism of osteogenesis, biomineralization and angiogenesis in the bone defect site under mild magnetic hyperthermia. Reproduced with permission [262].
Copyright 2022, Elsevier Ltd. All rights reserved.

microenvironment conducive to cell adhesion, which is critical for remains the primary clinical intervention, single-drug regimens face
functional cartilage regeneration. Similarly, Sun et al. [267] engineered limitations such as short half-lives and bleeding risks at high doses
porcine cartilage extracellular matrix-derived microcarriers to inhibit [269]. For example, 3–4.5 h after thrombus formation, clot compaction
inflammation and enhance cartilage regeneration in osteoarthritis impedes tissue-type plasminogen activator (t-PA) diffusion, thereby
models. Cell delivery and in vivo therapeutic results showed that this reducing thrombolytic efficacy [270]. Similarly, excess urokinase-type
microcarrier could effectively inhibit inflammation and promote carti­ plasminogen activator(u-PA) disrupts cerebral hemostasis and in­
lage regeneration. creases hemorrhage risk [268]. Notably, restoring blood flow after
Overall, magnetic hyperthermia therapy-powered regenerative thrombolysis may induce ischemic reperfusion injury (IRI), which can
platforms exhibit transformative potential across diverse tissue engi­ exacerbate tissue damage [271]. In addition to thrombolysis, post­
neering applications by integrating immunomodulation with function­ interventional modulation of the thrombotic microenvironment repre­
alized biomaterial design. In osseous reconstruction, these systems sents another critical aspect of vascular remodeling. This
coordinate macrophage polarization toward regenerative phenotypes or microenvironment contains elevated reactive oxygen species, primarily
utilize nanocomposites with core-shell structures to spatially control hydrogen peroxide, generated by activated platelets and damaged
immunometabolic cues, thereby synchronizing functional angiogenesis endothelial cells near occlusion sites [272]. Excessive reactive oxygen
with mineralized matrix deposition. The advancement of 3D bioprinting species trigger the pathological overexpression of inflammatory factors
technology further enables spatiotemporally controlled magnetic hy­ in vascular endothelial cells, which aggravates thrombosis and de­
perthermia therapy for enhanced osteogenic regeneration. Additionally, teriorates vascular integrity [273]. Therefore, removing excess reactive
precisely engineered magnesium ion release facilitates urothelial oxygen species from thrombi becomes essential for effective thrombo­
regeneration, and adaptable extension to neural repair via magneto­ lytic therapy. Thus, combined strategies enabling controlled and tar­
electrically enhanced axonal guidance. In the future, multimodal com­ geted thrombolytic drug delivery are urgently needed.
bination therapy based on magnetic hyperthermia therapy will add new
vitality to the field of tissue regeneration. 4.5.1. Thrombolysis through magnetic hyperthermia-based combination
A partial summary of tissue regeneration-associated magnetic therapy
nanomaterials is shown in Table 6, which shows the types of tissues that Research has shown that magnetic guidance enables reproducible
these magnetic nanomaterials can act on, their functions, and their targeted thrombolysis with <20 % of the conventional rt-PA dose [274].
dominance. More importantly, magnetic targeting offers precise nanoparticle de­
livery to occluded thrombi, independent of blood flow or pressure gra­
4.5. Thrombolysis dients, enabling remote control of MNPs [275]. Then, MNPs further
facilitate localized drug release and thermal therapy, which reduces
Thromboembolism, a global health concern and common post­ thrombolytic doses and effectively accelerates clot dissolution [276].
operative complication, arises from the rupture of unstable atheroscle­ Consequently, magnetic hyperthermia therapy offers promising avenues
rotic plaques, leading to myocardial infarction, stroke, and related for thrombolysis.
conditions [268]. While pharmacological thrombolysis (e.g., t-PA, u-PA) Strategies for the targeted delivery strategies of magnetic

Table 6
Tissue regeneration-associated magnetic nanomaterials.
Tissue Material Function Dominance Ref.

Bone Magnetized nanocomposite hydrogels Leads to optimized immunomodulatory bone Timed regulation of macrophage polarization. [254]
healing.
Others CS/PVA/HA/pSPIONs scaffold Enhanced cellular adhesion, proliferation, and Integrating the distinct advantages of magnetic hyperthermia [258]
3D-printed Fe3S4/AKT scaffold alkaline phosphatase expression, promoting bone therapy and hydrogels unlocks synergistic therapeutic [259]
A MION-RGD/agarose hydrogel regeneration. capabilities. [262]
Joule-Assisted Nanotherapeutic ROS-driven tumor eradication combined with Converges the complementary advantages of magnetic [263]
Urethral Stent (JANUS) magnetothermal-triggered metal ion release hyperthermia therapy (spatiotemporally controlled heating) [266]
Thermoresponsive liposomes accelerates functional bone regeneration. and chemodynamic therapy (site-specific ROS-mediated
encapsulating spider silk fibers coated Significantly enhances osteogenesis and cytotoxicity).
with ferromagnetic nanoparticles angiogenesis, dramatically accelerating new bone Enhances osteogenesis by integrating angiogenesis and
formation. immunomodulation.
Inhibits bacterial proliferation and promotes Integrates magnetic hyperthermia therapy with chemotherapy
endothelial regeneration to treat urinary tract leverages synergistic advantages.
strictures. Combines the exceptional biocompatibility and tunable
Autologous matrix-induced chondrogenesis physicochemical properties of biodegradable polymers with
(AMIC). the versatile functional attributes of nanoparticles.

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nanocomposites to thrombus sites, such as platelet-specific antibodies, microenvironment. This strategy not only overcomes the limitations of
external magnetic navigation, and erythrocyte hitchhiking mechanisms, single-modality thrombolysis but also modulates the postthrombolytic
enhance drug delivery precision and significantly improve therapeutic vascular microenvironment, potentially pioneering novel combinatorial
efficacy. Harper et al. [277] synthesized magnetic iron oxide nano­ therapeutic approaches based on magnetic hyperthermia therapy. Ul­
particles conjugated with commercial PAC-1 antibodies, which specif­ trasound thrombolysis mechanically disrupts clots via the cavitation
ically bind activated integrin αIIbβ3. This platelet fibrinogen receptor is effects of microbubbles [285]. However, the instability and poor tar­
exclusively expressed on activated human platelets, enabling precise geting ability of microbubbles restrict precise rt-PA delivery [286]. To
IONP targeting to thrombus surfaces. In vitro studies demonstrated that address this problem, Han et al. [287] developed disc-shaped magne­
targeted heating at thrombus surfaces enhanced thrombolytic efficiency toacoustic particles (rmDPPs) loaded with rt-PA and SPIONs. These
through two mechanisms: direct thrombus dissolution and increased tPA particles magnetically target clots and burst-release rt-PA under acoustic
fibrinolytic activity. Additionally, thermal effects increased thrombol­ stimulation, significantly reducing infarct size in photothrombosis
ysis efficiency by disrupting erythrocytes on thrombi, because they models.
enhanced tPA permeability. Notably, localized thermal delivery to
thrombi structurally destabilized clots, whereas an increase in the 4.5.2. Magnetic nanorobots
macroscopic temperature entirely failed to compromise endothelial cell Magnetic nanorobots (MNRs) provide a minimally invasive solution
viability, confirming the excellent biosafety of this thrombus-targeted for treating vascular blockages, particularly in deep, narrow vessels,
magnetothermal strategy. Furthermore, to address irreversible owing to their compact size and precise motility control [288–291].
ischemic-reperfusion injury (IRI) during thrombolysis, Xu et al. [278] Inspired by natural organisms, researchers have engineered MNRs with
engineered a magnetically targeted drug delivery system: Fe3O4@MP­ advanced propulsion and adaptive responsiveness to environmental
DA-Sr-TNK nanoparticles (FeM@Sr-TNK NPs). These NPs feature a cues, enabling autonomous collective behavior and coordinated func­
magnetic mesoporous polydopamine (MPDA) shell with broad-spectrum tionality [292,293]. These capabilities position MNRs as promising
antioxidant activity against reactive oxygen/nitrogen species (RONS), platforms for targeted drug delivery to thrombus sites. Significant efforts
and encapsulate Fe3O4 nanoparticles, strontium ions (Sr2+), and ten­ have focused on leveraging MNRs for efficient thrombolysis [294–296].
ecteplase (TNK). Under magnetic guidance, they achieved In previous studies, light-driven micromotors cloaked in platelet or
thrombus-specific localization, as validated by real-time photoacoustic erythrocyte membranes were shown to localize to thrombi through
imaging. Upon alternating magnetic field exposure, photothermal en­ biomimetic interactions and deliver drugs with spatiotemporal precision
ergy and TNK release synergistically enhance thrombolytic efficiency. [297]. Similarly, chemotactic neutrophils equipped with urease motors
Ultimately, during postrecanalization reperfusion, MPDA-mediated have demonstrated targeted thrombus homing and thrombolytic
RONS scavenging combined with Sr2+-driven vascular regeneration enhancement via u-PA delivery [291]. However, while these strategies
enables long-term repair of ischemia-reperfusion injury. Additionally, improve thrombolytic efficiency and drug bioavailability, their propul­
nanocarriers engineered for erythrocyte-mediated transport signifi­ sion mechanisms often lack sufficient force for rapid targeting, limiting
cantly accumulate at thrombus sites, which prolong the circulation their utility in single-robot operations. This delays clot accumulation
half-life and prevent hemorrhagic complications by eliminating repeti­ and impedes time-critical thrombolysis. In contrast, magnetic MNRs
tive high-dose administrations within short timeframes [279]. Chen show exceptional potential for rapid thrombolysis by either: mechani­
et al. [280] innovatively engineered bionic erythrocyte membrane cally disrupting local fluid dynamics to enhance thrombolytic drug
(EM)-camouflaged nanocapsules (USIO/UK@EM) with dual photo­ diffusion [289,295,298] or navigating external magnetic fields to
thermal/magnetothermal properties (Fig. 10a). These nanocapsules deliver drugs precisely to thrombus sites [299,300]. In 2020, He et al.
encapsulate ultrasmall iron oxide (USIO) and the thrombolytic drug [296] developed a biomimetic magnetic microrobot (BMM), a non­
urokinase (UK). Leveraging natural erythrocyte membrane-derived swelling microgel embedded with magnetic vesicle-like structures, for
stealth properties, the nanocapsules achieve immune evasion capa­ targeted microvascular thrombolysis via magnetic aggregation control
bility and significantly reduce reticuloendothelial system (RES) uptake (Fig. 10b). In this system, MNP chains enable magnetosensitive pro­
to extend the duration of blood circulation. This strategy achieved pulsion and amplify thrombolytic effects through collective motion.
thrombolysis rates of 82.4 % (venous) and 74.2 % (arterial) in mous­ Postmagnetic hyperthermia therapy, BMM swarms loaded with t-PA
e/rabbit models, far exceeding those of free UK (15 %). Compared with localize precisely at thrombus sites, enhancing clot dissolution syner­
the clinical UK coating, the EM coating extended the circulation half-life gistically. Similarly, Zheng et al. [295] created a magnetic nanoparticle
to 3.28h (t1/2 ≈ 20 min), which increased thrombus enrichment. swarm (MNS) platform guided by a C-shaped magnetic actuator for
In addition, combining MHT with other advanced therapies en­ active thrombolysis. Under an AMF, iron oxide nanoparticles assemble
hances thrombolytic efficacy. External stimuli such as ultrasound (US) into transportable microclusters that navigate from flowing vessels to
[281], and near-infrared (NIR) lasers [282] enable thermal converters to occluded branches. These microclusters deliver t-PA to thrombi via
increase local temperatures. MNPs or nanoclusters in these converters disrupted blood flow, and their oscillatory motion enhances t-PA
respond to NIR lasers to generate heat. While photothermal thrombol­ penetration into thrombi. Moreover, Zhang et al. [289] introduced a
ysis faces laser penetration limitations, rendering it primarily suitable hybrid magnetic torque-force strategy to navigate helical robots in dy­
for superficial thrombi such as peritoneal vein thrombi, magnetic hy­ namic flow environments. Doppler signals generated by rotating helical
perthermia therapy enables MNPs to penetrate deeper thrombosed re­ robots enabled real-time localization, demonstrating that
gions [283]. Guan et al. [284] engineered a multifunctional imaging-guided navigation accelerates thrombolysis with t-PA.
Fe3O4@MC-DEA-PBAP (FMDP) nanoplatform, which synergizes However, to overcome postthrombolysis retrieval challenges which
magneto-photothermal thrombolysis with biomimetic erythrocyte tar­ accumulated nanorobots may reduce efficacy or cause complications,
geting. The key steps involved: metal-organic frameworks crosslinked Guan et al. [301] designed MNRs with a heparin-like polymer brush
with CaCO3/PDA (CP) to form MC, which was subsequently function­ (HPB-NR) biointerface for safe and targeted thrombolysis (Fig. 10c).
alized with 2-(diethylamino) ethyl methacrylate (DEA) and 4-hydroxy­ These MNRs exhibit excellent dispersion, strong propulsion, and precise
phenylboronic acid pinacol ester (PBAP), followed by Fe3O4 navigation while carrying high drug loads. After treatment, they disas­
nanoparticle loading. After intravenous injection under magnetic navi­ semble into individual particles and are cleared by immune cell clear­
gation, the FMDP leverages DEA-mediated erythrocyte antigen binding ance, guaranteeing biosafety. Similarly, Zhang et al. [302] developed
for thrombus targeting. Near-infrared irradiation then triggers localized retrievable Fe3O4@mSiO2 nanorobot microclusters anchored with t-PA.
hyperthermia for thrombolysis, with PBAP subsequently scavenging Guided by magnetic actuation and fluorescence imaging, these clusters
reactive oxygen species to rehabilitate the postthrombotic vascular deliver t-PA via an expandable catheter and are retrieved postmission by

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Fig. 10. Schematic representation of updated protocols for targeted thrombolysis with magnetic nanomaterials. (a) Synthesis and mechanism of USIO/
UK@EM [280]. Copyright 2024, Wiley-VCH GmbH. (b) Schematic representation of the BMM with magneto-collective regulation for targeted thrombolysis. Mag­
netosomes in MTB act as the compass to respond to the geomagnetic field. MNPs assembled into the chain-like structures in microgels similar to the magnetosomes
after exposure to the external static magnetic field. The hydrogel shell provided biocompatible surface matrix and the MNP chains played the role in propulsion and
navigation. The BMM could be individually and collectively controlled and driven by the external rotating magnetic field to generate speedy motion response with
accurate positioning. The tPA-loaded BMM swarm demonstrated enhanced collective functions under alternating magnetic field. Reproduced with permission [296].
Copyright 2020, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Schemes illustrating the biosafety, drug loading of swarming HPB-NRs based on MB@PSS NPs
as building blocks. Reproduced with permission [301]. Copyright 2023, The Authors. An individual MB@PSS NP with loaded drugs and conjugated AT III i), a
heparinoid-PSS brush ii), loading tissue-type plasminogen activator (t-PA) drugs iii), and conjugating AT III iv) with PSS brushes via high affinity. v) Strong elec­
trostatic repulsions among neighboring MB@PSS NPs and between MB@PSS NPs and vascular wall, ensuring their strong anti-agglomeration, anti-bioadhesion, and
high biosafety in blood flows.

navigating back to the catheter tip. Wang et al. [303] further advanced coating, and an external magnetic control module [305].
retrievable systems. They demonstrated a scaffold-shaped magnetic MNPs can be designed for controlled drug release at targeted sites
soft-body robot. It self-anchors securely, navigates precisely under blood through responsiveness to specific biological stimuli (e.g., molecules
flow, carries thrombolytics, and doubles as a shunt to divert flow from [306] or cells [307]), physicochemical changes (pH shifts [308]), or
aneurysms. Ultimately, it can be recovered under magnetic field external triggers (magnetic field variations [309]). For example, Einaf­
navigation. shar et al. [310] proposed a nanocarrier with magnetic graphene oxide
In summary, cooperative strategies based on magnetic hyperthermia as the core, curcumin as the loaded drug, β-cyclodextrin (β-CD) to in­
therapy have significantly advanced thrombolytic therapy, progressing crease the solubility and cellular uptake of curcumin, and folic acid as a
from enhanced targeting precision of magnetic nanocomposites to syn­ functional modification layer for targeting folate receptors that are
ergistic integration with ultrasonic microbubbles and photothermal overexpressed on the surface of prostate cancer cells. The results showed
modalities. The remarkable potential of magnetic nanorobots in that this magnetic nanocarrier exerts concentration-dependent inhibi­
thrombolytic therapy has also been broadly explored and validated. tory effects on cell proliferation and the induction of oxidative damage.
However, in the field of thrombolysis, magnetic hyperthermia therapy Furthermore, nanoparticle relaxometry measurements confirmed its
still has many limitations that need to be gradually addressed in the utility as a negative contrast agent in MRI. Moreover, MNPs enable
future through a combination of more basic research and advanced precise drug targeting to diseased sites via specific cellular tropism. Hao
technology. et al. [307] reported a novel magnetic nanosystem using living stem
A partial summary of thrombolysis-associated magnetic nano­ cells, nanocarriers, and therapeutic agents. The system employs meso­
materials is shown in Table 7, which shows how these magnetic nano­ porous silica-coated superparamagnetic Fe3O4 nanoparticles
materials work, their functions, and their dominance. (Fe3O4@MSNPs) as carriers, which are bioconjugated to human
adipose-derived stem cells (hADSCs) via anti-CD44 antibodies. This
5. Delivery and release of targeted drugs engineered platform leverages the tumor-tropic properties of hADSCs
for targeted doxorubicin delivery, ultimately inducing significant
In the era of personalized precision medicine, conventional "carpet- apoptosis of Michigan Cancer Foundation-7 (MCF-7) tumor cells. The
bombing" drug delivery methods are being phased out. Magnetic PH of the tumor microenvironment is lower than that of normal tissues.
nanosystems engineered from MNPs now serve as smart vector systems This acidic condition can trigger drug release from MNPs. Fathi et al.
that enable precision-targeted drug delivery and controlled release to [311] utilized mint plant extract for the eco-friendly biosynthesis of
lesions through magnetic navigation. These systems significantly reduce magnetic Ag bio nanoparticles (M− Ag bio-NPs). These nanoparticles
drug distribution in healthy tissues, thereby lowering side effects while were incorporated into hybrid hydrogels composed of
enhancing therapeutic efficacy [304]. Biodegradable MNPs ensure kappa-carrageenan (k-Cr) and chitosan (CS) to form magnetic nano­
timely metabolic clearance, mitigate long-term toxicity risks and composite hydrogels. Crucially, CS demonstrates high solubility in
improve biosafety. Structurally, these nanosystems generally comprise dilute acidic solutions below pH 6.0 while maintaining excellent
five core components: a magnetic nanoparticle core, a drug-loading biocompatibility with living tissues, enabling the development of
layer, a functionalized surface modification layer, a biocompatible pH-sensitive CS-based hydrogels. Furthermore, doxorubicin-loaded

Table 7
Thrombolysis-associated magnetic nanomaterials.
Means Material Function Dominance Ref.

MHT-based Fe3O4@MPDA-Sr-TNK Provide efficient thrombolysis while address Precision navigation of magnetic field, [271]
combination nanoparticles irreversible ischemic-reperfusion injury (IRI). clear RONS to avoid IRI after thrombolysis, [277]
therapy IONPs conjugated with PAC-1 Coordinate thrombolysis expeditiously. combined hyperthermia and drug thrombolysis. [280]
antibody. Improve the performance of pharmacologic Target thrombi sites using specific antibodies,
USIO/UK@EM thrombolysis. no significant temperature increase, with superior
biosafety.
Achieve synergistic treatment with drug and magnetic
hyperthermia therapy to productively dissolve thrombus,
Magnetic Fe3O4@MC-DEA-PBAP Successfully remove blood clots and modulate the significantly reduce reticuloendothelial system (RES) [284]
Nanorobots (FMDP) nanoplatform postthrombolytic vascular microenvironment. uptake to extend blood circulation duration. [296]
A biomimetic magnetic Enable intelligent, collective, precise thrombolysis. Combined application of magneto-thermal and [301]
microrobot with tPA loads. Carry drugs for active thrombolysis. photothermal therapy,
HPB-NR prevent vascular damage caused by reactive oxygen
species.
Targeted deliver and release of thrombolytic drugs via
magneto collective control.
Exhibit excellent dispersion, strong propulsion, precise
navigation, and high drug loads,
ensure good biosafety with disassembly capability.

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magnetic nanocomposite hydrogels exhibited remarkable antitumor strategy reverses "cold tumors" and significantly enhances the efficacy of
activity. MNPs can also be remotely controlled through external mag­ subsequent immunotherapy.
netic fields and enable targeted drug delivery to specific diseased re­ Furthermore, developing biodegradable MNPs is crucial for
gions. Previous microrobot strategies for drug delivery to brain tumors enhancing therapeutic safety. This approach prevents prolonged MNP
have focused primarily on the circulatory system [312,313]. The limi­ retention in vivo, thereby mitigating potential long-term toxicity risks.
tations of these methods arise from rapid arterial blood flow (>1 m/s) Nguyen et al. [324] developed Fe3O4 nanoparticles with surface func­
and obstruction of the blood-brain barrier. Additionally, the diverse tionalization by lignin, achieving ciprofloxacin loading via electrostatic
populations of immune cells in the blood pose challenges for evasion of adsorption. The biodegradable nature of lignin prevents nanoparticle
immune clearance. Conversely, the relatively static and low-viscosity accumulation in vivo and associated toxicity risks. This magnetic drug
cerebrospinal environment provides favorable conditions for delivery system achieves natural metabolic clearance after exerting ef­
controlled microrobot navigation. To address these constraints, Xu et al. fects, substantially enhancing biosafety.
[314] developed magnetically driven biohybrid blood hydrogel fibre Thus, MNPs present significant advantages in targeted drug delivery
(BBHFs) engineered from MNPs integrated with patient-derived blood and controlled-release applications. By enabling precision transport of
components. Under precise magnetic guidance, BBHFs execute multi­ therapeutics to diseased sites, they enhance treatment efficacy while
modal locomotion across cerebrospinal fluid or brain surfaces. Criti­ minimizing off-target effects on healthy tissues. Concurrently, MNPs
cally, their rapid fragmentation under high-intensity magnetic fields pioneer new pathways for precision medicine, facilitating customized
enables on-demand release of encapsulated therapeutics such as doxo­ therapeutic dosing and spatiotemporal release profiles. However, the
rubicin. Through in vivo studies in a porcine model, drug-loaded BBHFs clinical implementation of personalized pharmacotherapy necessitates
demonstrated significant tumor growth suppression. further refinement of targeted and controlled-release technologies.
Magnetic micro/nanorobots have proved considerable promise in Although phased research breakthroughs have been achieved, large-
targeted drug delivery and release systems [315]. These versatile robots scale clinical trials remain imperative to validate their safety and effi­
can be engineered into diverse structures, including film millirobots cacy profiles, accelerating bench-to-bedside translation of these
[316] and nanoparticle collectives [317]. To fully understand their po­ innovations.
tential in targeted drug delivery and release, it is essential to recognize
their magnetic control systems and methods. Earlier work introduced a 6. Clinical trials of MNPs-MHT
method for arbitrary planar paths following the use of features extracted
in the image space as feedback, however, this single-locomotion MNPs-MHT has gained significant attention for its role as a focal
approach proved inadequate for complex in vivo environments [318]. nanothermal agent in tumor treatment [325]. Below, we summarize
To overcome this limitation, Xu et al. [319] pioneered a strategy for recent progress in MNPs-MHT clinical trials, with a focus on antitumor
multimodal locomotion control of needle-like microrobots assembled applications (Fig. 11).
from ferromagnetic nanoparticles under an AMF. Crucially, they The first MNPs-MHT clinical system was developed in 2000 at
developed a visual feedback path-tracking method enabling accurate Charité Medical School (Berlin), with NanoTherm® therapy pioneering
trajectory control—the crux of magnetic targeted drug delivery plat­ global trials for prostate and brain tumors. Jordan et al. later advanced
forms. Additionally, they established a magnetic control system this work by introducing an AMF therapy system [28]. Between 2003
comprising multiple magnetic soft millirobots and electromagnetic coils and 2005, a phase I trial involving 14 GBM patients demonstrated uni­
[320]. These robots exhibited completely decoupled motion control, form MNP distribution in tumors and validated the feasibility of MHT
incorporating independent control designs with four distinct magneti­ [326–328]. A subsequent phase II trial began in 2005 and remains
zation orientations. In subsequent experiments, they developed a ve­ ongoing. In 2007, Maier Hauff et al. [329] injected IONPs into 14
locity response model for these robots under oscillating magnetic fields recurrent GBM patients, achieving local tumor suppression via AMF
and experimentally validated it. This magnetic control system utilized heating (average 44.6 ◦ C, range 42.4◦ C-49.5 ◦ C). By 2010, MHT
visual feedback to achieve position control for up to 4 robots, and tra­ (branded as MagForce NanoTherm®) received European Medicines
jectory tracking control for up to 3 robots, laying a methodological Agency approval for recurrent glioblastoma [330] and FDA investiga­
foundation for pioneering targeted drug delivery magnetic nanorobots. tional device exemption for prostate cancer in 2018 [331]. Imai et al.
MNPs can also be designed as targeted drug delivery and release [331] conducted a 2013 phase I trial for head, neck, and breast cancers,
systems with dual active-targeting capabilities. Lu et al. [321] designed in which residual tumors were resected post-MNP injection for patho­
trilaurin-based lipid nanoparticles (LNPs) loaded with microfluidized logical analysis. In 2015, MagForce USA installed the first U.S. Nano­
dextran microgels encapsulating cisplatin/SPIONs. Upon oral adminis­ Activator® system [331]. A 2016 case report highlighted a significant
tration, these LNPs safely reach the colonic lumen. When dextranase, inflammatory response in the resection cavity of a recurrent glioma
which is exclusively present in the colon enzymatically degrades dextran patient treated with MHT, underscoring the need for vigilance regarding
microgels, the liberated LNPs become readily recognizable and inter­ potential side effects and the development of mitigation strategies. In
nalized by folic acid receptor-overexpressing colon cancer cells. This 2019, MagForce USA, Inc. completed enrollment and treatment for
dual active-targeting drug delivery system achieves precise elimination Stage I of its pivotal single-arm study evaluating NanoTherm® therapy
of colon cancer cells. In addition, dual-targeting systems combining for focal ablation of intermediate-risk prostate cancer, which paved the
magnetic guidance and homologous tumor cell membrane targeting can way for subsequent phases [28]. By 2021, NanoTherm® therapy ach­
enhance both MNP accumulation in tumor sites and targeted drug ieved notable advancements in glioblastoma treatment, successfully
release. Tumor-associated fibroblasts (TAFs) drive immunosuppressive completing phase 2a clinical trials [332]. Further progress in safety
"cold" microenvironments that severely compromise antitumor immu­ evaluation was made in 2024, when Rouni et al. [333] developed a
notherapy [322]. Cheng et al. [323] encapsulated salvianolic acid B computational model to predict skin surface temperature changes dur­
(SAB), an agent that inhibits TAF activation and reduces extracellular ing AMF-induced MHT. Their findings demonstrated strong alignment
matrix deposition, within porous magnetic nanoparticles (PMNPs). between numerical predictions and experimental measurements, vali­
These PMNPs were further modified with red blood cell membranes dating the model’s accuracy and establishing a framework for address­
(RBCM) and TAF membranes (TAFM) to construct multifunctional bio­ ing future MHT safety challenges.
mimetic nanoparticles (PMNP-SAB@RTM). RBCM prolongs the circu­
lation time of nanoparticles, whereas TAFM enables homologous 7. Challenges and perspectives
targeting to TAFs. Under precise external magnetic guidance,
PMNP-SAB@RTM actively accumulates at TAF sites to release SAB. This This review summarizes the physical heat-generation mechanisms of

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Fig. 11. Major events associated with the clinical trials of MNPs-MHT. The above chart documents the progress of clinical trials and research on MNPs-MHT in
countries around the world since 2000.

magnetic hyperthermia therapy, the types of magnetic nanoparticles the one hand, nanoparticle synthesis typically demands high-purity raw
and conductive nonmagnetic materials, and methods to enhance the materials and advanced equipment, whereas large-scale production
magnetic-thermal conversion efficiency of magnetic nanoparticles. This suffers from insufficient process stability. On the other hand, con­
work highlights the biological effects and biomedical applications of structing nanocomposite platforms involves multiple complex physical
multimodal combination therapy based on magnetic hyperthermia or chemical reactions, necessitating further research into the underlying
therapy, as well as the application of engineered magnetic nanoparticles mechanisms involved. Consequently, controllable fabrication of nano­
in targeted drug delivery and controlled release. Furthermore, the “hot- platforms with homogeneous morphologies remains as a formidable
spot” effects of magnetic hyperthermia therapy in clinical trials are challenge and requires further in-depth exploration. In the future, uni­
described. Although MNPs-MHT has advanced rapidly in the biomedical form nanoparticle size and morphology may be achieved by regulating
field, accelerating its clinical translation still requires overcoming a se­ preparation processes through microfluidic technology or template-
ries of challenges. A summary of the challenges and perspectives for based methods. The implementation of in situ characterization tech­
magnetic hyperthermia therapy is shown in Table 8. niques such as dynamic light scattering and X-ray diffraction can
The primary critical task involves enhancing the therapeutic efficacy monitor synthesis progression, concurrently enabling the establishment
and uniformity of MNPs-MHT. Currently, owing to safety consider­ of standardized production protocols. More critically, magnetic nano­
ations, clinical trials predominantly utilize low-dose MNPs, which fail to particles may undergo agglomeration under alternating magnetic fields.
achieve the optimal therapeutic temperature range (42–45 ◦ C). This Compelling evidence confirms that such aggregation-induced local
necessitates further optimization of the nanoparticle design and mag­ temperature unevenness substantially compromises hyperthermia effi­
netic field parameters. However, the efficiency of achieving adequate cacy [334]. Furthermore, agglomerated nanoparticles with increased
macroscopic temperature elevation through such optimization may hydrodynamic diameters face accelerated clearance by the reticuloen­
remain suboptimal. Thus, rationally leveraging the “hot-spot” effect, dothelial system. Their penetration into deep tumor tissues is concur­
characterized by rapid localized temperature spikes, may break current rently hindered by the elevated interstitial pressure and abnormal
bottlenecks in MNPs-MHT clinical translation. Exploiting this effect not vascular permeability of solid tumors, collectively diminishing their
only reduces the dependence on high-concentration MNPs but also targeting specificity. Moreover, biologically persistent nanoparticle ag­
serves as a "molecular switch" to control interactive molecular activities, glomerates resist efficient in vivo metabolism or degradation. Potential
thereby enabling targeted disease therapy. Nevertheless, substantial accumulation in vital organs such as the liver and spleen increase the
experimental validation and clinical trials are still imperative. Future risk of systemic toxicitity. Future approaches may involve surface
research should prioritize spatiotemporal control of hot-spots, combi­ modification of nanoparticles with polymers such as PEG, antibodies, or
nation therapies, and biosafety to advance clinical translation. Addi­ ligands to increase their dispersion stability and resistance to agglom­
tionally, achieving batch-to-batch uniformity in nanoparticle size, eration. Alternatively, the fabrication of nanoparticles with special
morphology, and magnetic properties remains challenging, significantly morphologies such as core-shell or porous architectures can reduce
impacting the thermal conversion efficiency and in vivo distribution. On interparticle interactions. Combining active targeting with magnetic

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Table 8 Table 8 (continued )

Challenges and perspectives for magnetic hyperthermia therapy. Category Specific Challenges Future Perspectives
Category Specific Challenges Future Perspectives
immunotherapy
Therapeutic Efficacy Clinically administered Optimization of regimens;
Nanoparticle low-dose MNPs nanoparticle design and implementation of
Fabrication and inadequately achieve magnetic field magnetic resonance-
Distribution optimal therapeutic parameters; rational guided magnetic
Uniformity temperature ranges exploitation and precise hyperthermia therapy;
Biocompatibility and (42–45 ◦ C). spatiotemporal control of screen for
Toxicity Difficulty in achieving “hot-spot” effects. immunotherapy-relevant
Lack of Clinical batch-to-batch uniformity Application of biomarkers.
Standardization in size, morphology, and microfluidic technology Integration of tissue-
Lack of Real-time magnetic properties; or template-based engineered scaffolds with
Monitoring insufficient process methods; establishment gene/cell therapies; AI-
Mechanistic Research stability. of standardized driven control systems
in Combination Aggregation under production protocols. enable real-time
Therapies alternating magnetic fields Surface modification, monitoring and dynamic
Dosing and temporal causes uneven heating and special morphology modulation of
optimization in reduced efficacy. designs, and combining hyperthermia
Combination Undefined long-term active targeting with parameters; AI-powered
Therapies biocompatibility and magnetic targeting image recognition
Potential cumulative potential toxicity risks due strategies to reduce technologies automate
toxicity risks in to nanoparticle aggregation. the analysis of tissue
Combination accumulation and immune Development of regeneration progress,
Therapies responses. degradable materials, accelerating mechanistic
Biomedical Variability in fabrication surface modifications, research and clinical
Applications protocols, administration long-term clinical follow- translation.
routes, and magnetic field ups, and personalized Develop intelligent
parameters, limiting treatment regimens. nanobiointerfaces
comparability. Development of enabling real-time
Absence of in vivo real- standardized clinical hemodynamic
time monitoring methods operational procedures adaptation, translate
for nanoparticle and unified treatment proof-of-concept designs
concentration and parameters. into large-animal trials
temperature distribution. Integration of multimodal addressing complex
Insufficient understanding imaging technologies vascular anatomies, and
of synergistic mechanisms (MRI, infrared establish regulatory
at cellular and molecular thermography, frameworks for clinical
levels or molecular fluorescence imaging) implementation.
interactions in and machine learning
combination therapies. models for dynamic
Lack of unified standards monitoring. targeting strategies further mitigates nonspecific aggregation. From a
for optimal dosing ratios Conduct multi-omics biosafety perspective, the use of degradable magnetic materials or sur­
and administration studies (transcriptomics,
face coatings decreases immunogenicity and toxicity, and clinical trials
sequencing in combination proteomics) to elucidate
therapies. synergistic mechanisms. should monitor indicators including hepatic/renal functions and in­
Combinatorial approaches Mathematical modeling flammatory cytokine levels.
might amplify MNPs- and clinical trials for dose A critical barrier to clinical translation of MNPs-MHT remains the
related biohazards (e.g., ratio optimization and undefined long-term biocompatibility and potential toxicity of MNPs,
nanoparticle sequential
accumulation) and side administration,
including organ accumulation and immune responses, which necessi­
effects from co- comprehensive safety tates validation through large-scale cohorts with long-term follow-up. In
administered therapies assessment. addition to current approaches such as developing self-regulating MNPs
(such as chemotherapy- Intensified research focus with targeting capabilities to minimize tissue damage and organ accu­
induced systemic toxicity). on comprehensive long-
mulation or exploring MHT combination therapies to overcome mono­
Antitumor Therapy term safety assessments,
Antibacterial Action particularly evaluating therapy limitations, personalized MNPs dosing regimens and magnetic
Immunomodulation multiorgan functional parameters could be tailored according to patient-specific genetic pro­
Tissue Regeneration impacts and chronic files and tumor microenvironmental metrics to ensure optimal
Thrombolysis alterations in immune biocompatibility. Alternatively, integrating resources from materials
activation dynamics.
Integrate ADCs therapy
science, biomedical engineering, and clinical medicine may accelerate
with magnetic the development of engineered MNPs with superior biocompatibility.
hyperthermia; Magnetic- Another significant challenge arises from substantial variations in MNP
plasmonic hybrid fabrication protocols, administration routes, and magnetic field pa­
hyperthermia.
rameters across studies, severely limiting comparability. Establishing
AI-guided dual-functional
AgNP-magnetic standardized clinical operational standards is consequently imperative.
composites that Moreover, the absence of real-time in vivo monitoring methods for MNP
simultaneously detect concentration, temperature distribution, or functional parameters of
bacteria and eradicate pathological tissues impedes precise dosage adjustment and efficacy
biofilms.
Leverage AI algorithms to
evaluation. Future approaches may integrate multimodal imaging
establish personalized techniques, such as high-spatial-resolution MRI and real-time infrared
therapeutic models to thermography, to achieve dynamic visualization of MNP distributions
predict optimal thermal and thermal fields. Further integration of highly sensitive/specific
dosages and
fluorescence imaging could facilitate precise diagnosis and therapeutic
monitoring, while fluorescent probes may quantify functional data (e.g.,

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metabolic activity, blood perfusion, and apoptosis) in tumor tissues, efficiency, whereas copper sulfide also provides biodegradability. These
offering comprehensive evidence for efficacy assessment. Encourag­ are critical criteria for clinical translation and long-term biomedical
ingly, machine learning models that integrate monitoring data to predict applications.
therapeutic outcomes and dynamically adjust magnetic parameters In the field of bacterial resistance, artificial intelligence-driven in­
present a promising strategy for optimizing real-time monitoring in novations will revolutionize this field. For example, machine learning
magnetic hyperthermia therapy. algorithms can optimize silver nanoparticle synthesis for amplified
Notably, clinical trials of combination therapies based on magnetic surface-enhanced Raman spectroscopy (SERS) detection, enabling real-
hyperthermia therapy continue to confront several universal challenges. time identification of foodborne pathogens such as Salmonella and
The primary obstacle is insufficient research on synergistic mechanisms. E. coli at a concentration of 1.1 CFU/mL [339]. AI-guided predictive
Most current combination strategies merely demonstrate superior ther­ models will further develop dual-functional AgNP-magnetic composites
apeutic outcomes compared with monotherapy, but lack a mechanistic that simultaneously detect bacteria through rapid optical signatures and
understanding of more in-depth effects at the cellular and subcellular eradicate biofilms via localized magnetic hyperthermia therapy or
levels or molecular interactions between distinct therapeutic modalities. plasmonic hyperthermia [340]. Such autonomous systems promise to
More studies must utilize multiomics approaches, such as tran­ establish intelligent food safety networks from farm to table, using
scriptomics and proteomics, to identify synergistic targets and prevent portable nanosensors that screen for microbial threats within seconds
potential antagonistic interactions. A secondary challenge involves dif­ while delivering on-demand decontamination, ultimately creating a
ficulties in dosing and temporal optimization. No unified standards exist preventive healthcare ecosystem.
for determining optimal dosing ratios between MNPs-MHT and other In the field of immunomodulation, the primary challenge stems from
treatments such as drug release systems or immune activation therapies, significant individual heterogeneity in immune responses, which in­
nor for sequencing their administration. For example, excessively high volves tumor microenvironment features, genetic mutation profiles, and
MNP concentrations may compromise nanocarrier structural integrity, baseline immune status. Critical knowledge gaps persist regarding syn­
whereas insufficient concentrations fail to trigger immune responses. ergistic mechanisms between magnetic hyperthermia effects and im­
Addressing this issue necessitates exploring optimal parameter combi­ mune activation, particularly the undefined quantitative relationships
nations through rigorous mathematical modeling and well-designed among thermal dosage, duration, and immune activation intensity.
clinical trials. Another critical issue is potential cumulative toxicity Additional obstacles include technical bottlenecks in clinical translation,
risks. Combinatorial approaches might amplify MNP-related biohazards exemplified by the lack of standardized immune monitoring metrics thus
(e.g., nanoparticle accumulation) and side effects from coadministered hampering efficacy assessment. Future efforts could leverage AI algo­
therapies (such as chemotherapy-induced systemic toxicity). Conse­ rithms to integrate patient genomic data, immune profiles, and magnetic
quently, intensified research should focus on comprehensive long-term hyperthermia parameters, establishing personalized therapeutic models
safety assessments, particularly evaluations of multiorgan functional to predict optimal thermal dosages and immunotherapy regimens. The
impacts and chronic alterations in immune activation dynamics. implementation of high-field-strength, high-homogeneity magnetic
In the future, advanced engineered MNPs will progressively expand resonance-guided magnetic hyperthermia therapy (MRgMHT) would
into broader biomedical domains, and the progressive maturation of enable real-time temperature monitoring and dosage modulation during
artificial intelligence and other emerging technologies holds the po­ therapy, while implantable micro-magnetic devices may achieve sus­
tential to provide disruptive momentum for magnetic hyperthermia tained localized immune activation of tumors via minimally invasive
therapy across broad-spectrum biomedical implementation. techniques. Screening for immunotherapy-relevant biomarkers associ­
Given the current challenges in cancer treatment, enhancing thera­ ated with magnetic hyperthermia responses, such as circulating tumor
peutic efficacy fundamentally requires improved drug targeting and DNA dynamics and immune cell subset ratios in peripheral blood, would
multimodal therapeutic approaches. Antibody-drug conjugates (ADCs) further facilitate outcome prediction and patient stratification.
represent a novel class of biologics that link cytotoxic drugs to targeting For the field of tissue regeneration, the future synergistic integration
antibodies via specialized chemical linkers. Researchers have validated of tissue-engineered scaffolds with gene/cell therapies promises diverse
the profound clinical efficacy of this therapeutic approach in treating therapeutic frameworks for complex tissue repair, particularly in neural
malignancies, including breast cancer and relapsed lymphoma [335]. and myocardial regeneration. AI-driven control systems enable real-
Furthermore, Ma et al. [336] proposed a groundbreaking translational time monitoring and dynamic modulation of hyperthermia parameters
study utilizing AI algorithm-driven modeling to explore predictive bio­ to ensure both safety and efficacy. Concurrently, AI-powered image
markers for ADCs in breast cancer. This significantly advances the recognition technologies may automate the analysis of tissue regenera­
development of ADC therapeutics. Integrating ADCs with MNPs through tion progress, accelerating mechanistic research and clinical translation.
surface functionalization can substantially increase the precision of drug With continued cross-disciplinary innovation, magnetic hyperthermia
targeting, thereby enhancing treatment outcomes. Additionally, therapy is poised to transition from laboratory research to widespread
single-modality magnetic hyperthermia therapy relies on heat genera­ clinical implementation, pioneering intelligent and transformative
tion through hysteresis loss or relaxation loss of magnetic materials pathways for regenerative medicine.
under alternating magnetic fields, with the heating efficiency con­ In the field of thrombolysis, while previous advances have demon­
strained by inherent magnetic properties. In contrast, plasmonic pho­ strated unprecedented spatial control and multifunctional capabilities,
tothermal therapy uses materials such as gold nanoparticles that convert key challenges persist regarding long-term biosafety validation across
absorbed light into thermal energy via localized surface plasmon reso­ physiological models and scalable manufacturing standards. Future
nance. Magnetic-plasmonic hybrid hyperthermia that integrates both research must prioritize intelligent nanobiointerfaces enabling real-time
approaches enables not only precise spatiotemporal thermal control but hemodynamic adaptation, translate proof-of-concept designs into large-
also concurrent implementation with MRI contrast enhancement or animal trials addressing complex vascular anatomies, and establish
AI-guided imaging systems, thereby improving therapeutic visualization regulatory frameworks for clinical implementation. Ultimately, the
and targeting accuracy. Platforms include developed hybrid colloidal convergence of adaptive robotics and artificial intelligence promises
nanostructures (mesoporous silica-coated gold nanorods with subse­ closed-loop thrombolytic systems with transformative potential for
quent iron oxide nanoparticle growth) [337] and Janus Au:Fe3O4 precision medicine.
nanostars or nanospheres [338], which all demonstrate exceptional In summary, magnetic hyperthermia therapy has distinct advantages
tumor suppression efficacy. Notably, copper sulfide and titanium nitride over conventional thermal therapies, particularly through its deep-
are emerging as promising alternatives to traditional plasmonic mate­ tissue penetration capability and remote activation mechanism. Never­
rials. Compared with gold nanoparticles, they offer superior cost theless, comprehensive clinical validation remains imperative to

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determine its therapeutic necessity, biological rationality, and techno­ Funding

logical superiority for targeted biomedical applications. This review
aims to consolidate fundamental principles while catalyzing innovative This work was supported by the National Natural Science Foundation
research pathways for emerging and established investigators. The of China (No. 82402780), the China National Postdoctoral Program for
accelerating translation of magnetically responsive platforms—from AI- Innovative Talents (No. BX20230350), the China Postdoctoral Science
controlled nanosystems to biodegradable implants—into clinical prac­ Foundation (No. 2024M753130), the Scientific Research Project of
tice promises transformative diagnostic-therapeutic integration for Anhui Provincial Health Commission (No. AHWJ2024Aa20475), Anhui
precision magnetic hyperthermia therapy. Postdoctoral Scientific Research Program Foundation (No. 2025B1048),
the Research Funds of Centre for Leading Medicine and Advanced
CRediT authorship contribution statement Technologies of IHM (No. 2023IHM02007).

Yu Chen: Writing – review & editing, Writing – original draft. Haifu Declaration of competing interest
Sun: Validation, Supervision, Software, Methodology. Yonggang Li:
Validation, Supervision, Software, Methodology. Xixi Han: Methodol­ The authors have declared that no competing interest exists.
ogy, Investigation. Yuqing Yang: Project administration, Conceptuali­
zation. Zheng Chen: Visualization, Methodology, Conceptualization. Acknowledgments
Xuequan Zhao: Formal analysis, Conceptualization. Yuchen Qian:
Methodology, Formal analysis. Xishui Liu: Validation, Software. Feng The figures in this review were partially created with BioRender.
Zhou: Writing – review & editing, Visualization, Supervision, Investi­ com. I am deeply indebted to my supervisor for the invaluable oppor­
gation, Conceptualization. Jiaxiang Bai: Writing – review & editing, tunities and academic platform, and profoundly grateful to my post­
Visualization, Supervision, Investigation, Conceptualization. Yusen graduate seniors for their indispensable support and intellectual
Qiao: Writing – review & editing, Validation, Supervision, Resources, enlightenment. Thanks to my most beloved older brother, mom and dad,
Funding acquisition, Conceptualization. grandmother for their concern and company, and my dearest aunt for
her consideration and healthy support.
Ethics approval and consent to participate

This review did not conduct animal experiments.

Abbreviations

MHT magnetic hyperthermia therapy

MNPs magnetic nanoparticles
AMF alternating magnetic field
MNPs-MHT MNPs-mediated MHT
PDT photodynamic therapy
ROS reactive oxygen species
H magnetic field intensity
M magnetization
Hc high coercivity
SPIONs Superparamagnetic iron oxide nanoparticles
TAMs tumor-associated macrophages
MRI magnetic resonance imaging
SAR specific absorption rate
TME tumor microenvironment
LMP lysosomal membrane permeabilization
ICD immunogenic cell death
HSPs heat shock proteins
QS quorum sensing
MGO magnetic graphene oxide
MNS magnetic nanoparticle swarm
ADCs antibody-drug conjugates
SERS surface-enhanced Raman spectroscopy

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