Materials Today Bio 33 (2025) 102070

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Materials Today Bio

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Magnetic hyperthermia in oncology: Nanomaterials-driven combinatorial

strategies for synergistic therapeutic gains
Linyan Xiong a,b, Bing Liang a,b,* , Kexiao Yu c,**
a
Department of Pathology from College of Basic Medicine, and Department of Clinical Pathology Laboratory of Pathology Diagnostic Center, and Molecular Medicine
Diagnostic & Testing Center, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, PR China
b
Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong Distinct, Chongqing, 400042, PR China
c
Department of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, The First Affiliated Hospital of Chongqing College of Traditional Chinese Medicine, No. 6
Panxi Seventh Branch Road, Jiangbei District, Chongqing, 400021, PR China

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

Keywords: Cancer cures remain limited with conventional treatments due to tumor microenvironment (TME)-driven
Cancer resilience and systemic toxicity. Magnetic hyperthermia therapy (MHT), which utilizes magnetic nanoparticles
Magnetic hyperthermia therapy (MNPs) to convert alternating magnetic field (AMF) energy into localized heat, has emerged as a minimally
History
invasive and spatially precise strategy for tumor ablation. This review critically examines the evolution of MHT
Mechanism
from its historical roots to cutting-edge combinatorial strategies. The unique advantages of MHT over other
Material
Combination hyperthermia modalities are firstly analyzed, highlighting its ability to synergize with the hypoxic and acidic
TME for enhanced tumor cell susceptibility. In addition, the pathophysiological mechanisms of cell death
induced by MHT were summarized in detail. Next, MHT-optimized nanomaterials are systematically classified
based on their heating efficiency, biodistribution, and functionalization strategies for tumor targeting. A key
focus lies in elucidating the multimodal therapeutic synergy between MHT and established oncology treatments:
(photothermal therapy [PTT], radiotherapy, chemotherapy, immunotherapy) and analyzed the clinical trans­
lational bottlenecks of each combination. Finally, the review delineates the translational roadmap of MHT by
addressing key bottlenecks in clinical adoption, including AMF device standardization, long-term MNP biosafety,
and scalable nanomanufacturing. This work provides a nano-biomaterials perspective to guide the rational
design of next-generation MHT platforms for precision oncology.

1. Introduction lactate levels, glucose deprivation, energy impoverishment, significant

interstitial fluid flow, and interstitial hypertension, defining the meta­
Cancer persists as a formidable global health threat with persistently bolic TME [5–7]. Crucially, this environment often renders tumor cells
high age-standardized incidence rate (186.5 cases per 100,000 popula­ resistant to chemotherapy and radiotherapy, further limiting the effi­
tion in 2022) [1,2]. While conventional therapies like chemotherapy cacy of these conventional methods. This situation compels the medical
and radiotherapy face significant challenges: their lack of specificity community to seek innovative therapies beyond the limitations of cur­
frequently damages healthy tissues, causing severe side effects; rent treatment approaches.
concurrently, the adaptive evolution of cancer cells and the unique Hyperthermia therapy (HT), including MHT, offers an alternative
physiology of tumors collectively contribute to the difficulty in strategy. Unlike chemo/radiotherapy, the hypoxic and acidic (low pH)
achieving sustained remission, particularly in non-resectable cases [3, TME can enhance tumor cells’ susceptibility to heat [8]. However,
4]. This distinct tumor physiology results from the loss of suppressor traditional MHT approaches utilizing larger magnetic particles
gene function and activation of oncogenes. It is characterized by features encounter inherent limitations: they typically require invasive surgical
including O2 depletion (hypoxia or anoxia), extracellular acidosis, high procedures for direct implantation into the tumor site, which restricts

* Corresponding author. Department of Pathology from College of Basic Medicine, and Department of Clinical Pathology Laboratory of Pathology Diagnostic
Center, and Molecular Medicine Diagnostic & Testing Center, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, PR China.
** Corresponding author. Department of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, The First Affiliated Hospital of Chongqing College of
Traditional Chinese Medicine, No. 6 Panxi Seventh Branch Road, Jiangbei District, Chongqing 400021, PR China.
E-mail addresses: doctorliang51@163.com (B. Liang), csyxk@126.com (K. Yu).

https://doi.org/10.1016/j.mtbio.2025.102070
Received 20 April 2025; Received in revised form 3 July 2025; Accepted 7 July 2025
Available online 9 July 2025
2590-0064/© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-
nc/4.0/).
L. Xiong et al. Materials Today Bio 33 (2025) 102070

their applicability, increases patient burden, and hampers treatment of core limitations of both conventional therapies and traditional MHT,
deep-seated or multiple lesions. Furthermore, large implants can also leveraging the unique superiority conferred by AMF and MNPs.
lead to issues like inhomogeneous heat distribution. As an external energy source, AMF exhibits strong penetration
In this context, nanotechnology-mediated thermal therapy, particu­ capability with minimal attenuation in biological tissues, making MHT
larly nano-MHT, has emerged as a significant breakthrough, demon­ suitable for treating deep-seated tumors—a stark contrast to the limited
strating distinct advantages. By applying an external AMF, MNPs tissue penetration of laser and microwave thermotherapy [10,11].
localized within the tumor transform electromagnetic energy into Concurrently, the physical thermogenesis mechanism of MHT enables
thermal energy. This effectively elevates the intratumoral temperature repeatable treatments, significantly reducing patient discomfort and
to cytotoxic levels (typically 42–46 ◦ C), selectively destroying cancer facilitating potential future outpatient tumor management. Compared to
cells [9]. Among various nano-thermal techniques (laser, microwave, implanting large particles, NPs can be administered via intravenous or
radiofrequency, ultrasound), AMF-mediated nano-MHT has garnered local injection in a minimally invasive manner, accessing diverse tumor
considerable attention in recent years. It systematically addresses the locations while generating heat more uniformly and efficiently.

Fig. 1. We introduce MHT from various aspects in this review. It includes the history, mechanisms and superiorities, and focuses on the latest advances in materials
and the advantages of combinational therapy for tumor killing.

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Functionalized MNPs can be engineered for active tumor targeting, in a rat model [18], further demonstrated the potential of MHT in
concentrating heat production within the tumor, minimizing damage to medical device applications, gradually expanding its scope from basic
surrounding healthy tissue, and thereby reducing systemic toxicity [12]. materials to practical medical uses. Furthermore, from 2003 to 2005,
Additionally, nanotechnology allows for precise control of heating by glioblastoma clinical trial at the University of Berlin confirmed the
adjusting parameters such as NPs composition, size, shape, and the safety of MF-mediated magnetic induction hyperthermia (MIH)
characteristics of the applied AMF, meeting diverse therapeutic needs [19–21], also marking an acceleration of clinical translation.
[9,13]. Moreover, nano-MHT synergistically enhances the efficacy of By 2006, surface-modified SPIONs had been applied to drug delivery,
chemotherapy/radiotherapy/immunotherapy: thermal energy remotely immunoassays, and transarterial chemoembolization of hepatocellular
activates drug release and amplifies chemotherapeutic cytotoxicity by carcinoma (TACE) [22], and the material platform was further expanded
increasing tumor cell membrane permeability, promoting trans­ in 2008 with nanothermal therapy technology and Ferucarbotran-based
membrane transport, and improving intratumoral blood circulation. arterial embolic hyperthermia (AEH) [23,24]. Current research on
Collectively, MHT demonstrates seven core characteristics: 1. MNPs for MHT focuses on optimizing the synthesis pathway, structural
Non-invasiveness; 2. Repeatability; 3. Localization; 4. Deep-tissue morphology and surface modifications to enhance the rate of heat pro­
penetration; 5. Effectiveness; 6. Personalization and 7. Combinatorial duction, monodispersity, cyclic half-life, targeting accuracy and
synergy, positioning it as a promising adjunct to conventional cancer biocompatibility [25,26].
therapies. Currently, clinical trials of magnetothermal therapy are being con­
This review chronicles the evolution of MHT, spotlighting its tumor- ducted primarily in prostate cancer and glioblastoma multiforme (GBM)
selective mechanisms driven by TME. We critically evaluate state-of-the- patients (Table 1). For instance, three-stage therapy for prostate cancer:
art nanomaterials optimized for heating efficiency, biodistribution, and (1) CT-based tumor assessment; (2) integrated tumor boundary and
functionalization. Furthermore, we dissect multimodal synergies be­ vascular system for particle dose/deposition calculation planning; and
tween MHT and conventional therapies—PTT, radiotherapy, chemo­ (3) ultrasound-guided transurethral injection of 12.5 mL of iron oxide
therapy, and immunotherapy—revealing their TME-remodeling actions solution (prostate volume of 35 mL), followed by radiofrequency MHT
and translational hurdles. We have summarized each section (history, treatment [27]. Similarly, the MHT combined with radiotherapy
mechanism, superiorities, materials and combination) for the theme of regimen for recurrent GBM achieved prolonged survival without side
MHT in Fig. 1. By bridging nanomaterial innovation with clinical im­ effects through tumor resection, stereotactic SPION delivery, and
peratives, this work charts a roadmap for next-generation MHT plat­ MRI/CT thermal border modeling [28]. These trials corroborate the
forms in precision oncology. synergistic potential of MHT, but technical bottlenecks remain.
High requirements for the development of magneto-thermal devices
2. History of MHT materials and clinical development of MHT (balancing safety and efficacy): the most used safety standard for AMF is
the Brezovich limit (H0f ≤ 4.8 × 108 Am− 1s− 1) [29], but it is often
Over the past seventy years, MHT has undergone significant devel­ difficult to achieve the target thermal efficacy at this limit. Bellizzi’s
opment, mainly driven by the continuous optimization of magnetic team proposes raising this threshold to 1.9 × 109 Am− 1s− 1 for the
fluids (MFs) and biomaterials (Fig. 2). In 1960, a crucial milestone was treatment of brain tumors, or to halve the nanoparticle dose [30].
set when NASA first utilized iron oxide nanoparticles (IONPs) [14]. NanoTherm® (aminosilane-coated Fe3O4 nanoparticles), approved
Their biocompatibility and subsequent FDA approval laid the founda­ as an adjuvant for GBM radiotherapy, prolonged median survival by 4.2
tion for MHT, making them a cornerstone material in this field [15]. months but was limited by a low specific uptake rate (738-985 pH-
Building on this, in 1985, Lilly et al. developed nickel-copper thermal m2⋅kg− 1), which required a high iron concentration of 112 mg mL− 1 to
seeds with a Curie temperature of 50 ◦ C for mesenchymal implant trigger MRI artifacts and nanoparticle leakage. Tumor osmotic pressure
thermotherapy [16], expanding the range of MHT applications. Then, in gradients exacerbate NPs redistribution, leading to off-target heating
2002, Rehman’s team made a breakthrough by creating ferromagnetic [31–33].
self-regulating heat seeds [17]. This innovation improved the tempera­ In addition, mild HT (39–42 ◦ C) induces overexpression of heat
ture control of MHT, enhancing its safety and effectiveness. In 2005, shock proteins (HSPs), triggering transient thermoresistance [34,35].
Shoi’s team developed a magnetic stent for bile duct stenosis. Their Although the minimally invasive and precise nature of MHT has clinical
research, which validated the safe heating of up to 45 ◦ C at 157 kHz AMF advantages, the above limitations require mechanistic studies to

Fig. 2. The development history of MHT materials.

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Table 1
Summary of clinical trials of MHT for tumor treatment.
Trial Cancer type Patient Injection Adjuvant AMF Maximum SAR Treatment results Year Reference
phase number route therapy strengths temperature &
Temperature
measurement method

I Glioblastoma 14 Intratumoral Radio/ 3.8 to 13.5 44.6 ◦ C(median) – MHT was well 2003 [249]
multiforme chemotherapy kAm− 1 (Invasive tolerated.
(median: temperature probing Only mild side effects
8.5) with thermal probes) were observed
I Prostate carcinoma 10 Transperineal – H = 100 48.5 ◦ C (Invasive 288 The patients were able 2005 [250]
kHz, f = 4 temperature probing W to tolerate an AMF
kAm− 1 with thermal probes) kg− 1 strength of 4–5 kAm-1.
Serum PSA levels
decreased in 8
patients after
treatment, and the
mean duration of PSA
control was 5 months
(3–8 months).
I Chondrosarcoma, 22 Transperineal Radio/ – 39.5 ◦ C (Intratumoral 130 Tolerable AMF 2006 [19]
sarcinoma cervical/ chemotherapy temperature W strengths:
prostate/ovarian/ monitoring via fiber- kg− 1 Pelvis:3.0–6.0 kAm− 1
rectal carcinoma optic probes) Chest and neck
area:7.5 kAm− 1
Head:>10.0 kAm− 1
II Glioblastoma 3 Intratumoral Radio/ H = 100 Patient 1:49.5 ◦ C/ – Low uptake of 2009 [244]
multiforme chemotherapy kHz,f = Patient 2 dead before aggregated particles
2.5–18 MHT/Patient in glioblastoma cells.
kAm-1 3:65.5 ◦ C High uptake of
(Intratumoral particles by
temperature macrophages.
monitoring via fiber- No clinically adverse
optic probes) effects.
II Glioblastoma 66 Intratumoral Radio/ H = 100 51.2 ◦ C (median) – The median overall 2011 [28]
multiforme chemotherapy kHz,f = (Intratumoral survival was 13.4
2–15 kAm- temperature months.
1
monitoring via
thermal probes)

Fig. 3. Patterns of tumor death under HT.

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optimize treatment. cells. Early hypotheses attributed HT-induced cytotoxicity primarily to

alterations in cell membrane integrity. Elevated temperatures destabi­
3. The mechanism of HT killing tumor lize membrane fluidity and permeability, impairing actin filament and
microtubule function. This destabilization disrupts facilitated diffusion,
In the field of cancer treatment, HT is emerging as a promising causing metabolite accumulation, intracellular fluid imbalance, and
therapeutic modality. An in-depth understanding of the tumor-killing eventual cell lysis [43]. However, current understanding emphasizes
mechanism of HT is crucial for optimizing treatment plans, improving that HT-induced apoptosis is mediated through three distinct pathways:
therapeutic efficacy, and promoting the development of medical the intrinsic (mitochondrial) pathway, the extrinsic (death receptor)
oncology. We present the known or possible mechanisms of tumor death pathway, and the less-characterized endoplasmic reticulum (ER) stress
under thermotherapy from multiple perspectives (Fig. 3). pathway [44]. Elucidating these mechanisms is essential for advancing
precision cancer therapies.
3.1. The direct effect of temperature on tumor While the precise mechanisms of HT-induced apoptosis remain
under investigation, studies suggest that the intrinsic pathway is central.
Studies have shown that irreversible cellular damage occurs in cell Mitochondrial ultrastructural changes—including cristae vesiculation,
lines or tissues only after prolonged exposure (30–60 min) to tempera­ swelling, and dense body formation—occur within minutes of heat
tures between 40 and 45 ◦ C [36]. Above 60 ◦ C, the time needed for exposure [45]. These alterations promote outer mitochondrial mem­
irreversible damage drops exponentially, with vital enzyme inactivation brane (OMM) permeabilization, regulated by Bcl-2 family proteins.
being the first sign. Rapid protein denaturation, which is cytotoxic and Pro-apoptotic members such as Bak and Bax induce OMM rupture,
leads to coagulative necrosis, occurs swiftly at these temperatures releasing cytochrome c and apoptosis-inducing factor (AIF) into the
(Fig. 4). However, a targeted in vivo tumor destruction is accomplished cytosol [46]. Subsequent apoptosome formation via Apaf-1 oligomeri­
within the temperature range of 40–44 ◦ C, a phenomenon linked to zation activates caspase-9, which cleaves effector caspases-3/7 to
distinct physiological differences between malignant and healthy cells. execute apoptosis. HT also enhances caspase-2 activation through
However, the targeted destruction of tumors within the body is achieved RAIDD complex formation, facilitating Bid cleavage into truncated Bid
within a temperature range of 40–44 ◦ C, and maintaining this temper­ (tBid), which amplifies cytochrome c release [47–49]. Furthermore, HT
ature range for 1 h typically does not cause damage to most normal primes Bax/Bak for activation by inducing conformational changes and
tissues. This phenomenon is linked to the distinct physiological differ­ upregulating JNK-mediated phosphorylation of pro-apoptotic Bim [50].
ences between malignant and healthy cells. The chaotic vascular ar­ HT concurrently modulates the extrinsic pathway by activating
chitecture within tumor tissue impairs its heat dissipation capacity, death receptors (e.g., Fas, TRAIL, TNF-α). Ligand-receptor binding ini­
while the hypoxic and acidic microenvironment further enhances tumor tiates caspase-8 activation, which either directly triggers effector cas­
cells’ susceptibility to HT [37–42]. pases or engages the mitochondrial amplification loop via Bid cleavage
[51]. Synergistic HT-TRAIL treatment in colorectal cancer cells en­
3.2. HT induces tumor cell apoptosis hances caspase-8/-9/-3 activation and cytochrome c release [52].
Similarly, TNF-α-TNFR1 interaction post-HT suppresses heat shock
Emerging evidence indicates that HT can induce apoptosis in cancer factor 1, reducing survival and promoting caspase-8-dependent

Fig. 4. Some pathways involved in tumor death under HT.

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apoptosis in macrophages. HT also induces ER stress by accumulating 3.5. HT promotes cuproptosis of tumor cells
misfolded proteins, activating the intrinsic ER apoptosis pathway
(Fig. 4). Collectively, HT engages multiple apoptotic cascades, under­ Recent advances in cell death research have identified cuproptosis, a
scoring its therapeutic potential. By delineating these mechanisms, re­ copper-dependent cell death mechanism distinct from apoptosis, nec­
searchers can optimize HT-based strategies to selectively target cancer roptosis, pyroptosis, and ferroptosis [61,62]. This process, driven by
cells while sparing healthy tissues [53]. intracellular copper accumulation, disrupts mitochondrial function by
inducing aggregation of tricarboxylic acid (TCA) cycle proteins and
destabilizing iron-sulfur (Fe-S) cluster proteins, culminating in proteo­
3.3. HT increases oxidative stress in tumor cells
toxic stress and cell death [63]. Elevated copper levels, frequently
observed in tumor tissues and serum of cancer patients, position
Heat stress is a well-documented inducer of oxidative stress in cells,
cuproptosis as a promising therapeutic target for malignancies such as
primarily through increased generation of reactive oxygen species
breast cancer, lung cancer, and melanoma.
(ROS). ROS, including superoxide anion (O2− ), hydrogen peroxide
Current strategies to induce cuproptosis focus on enhancing mito­
(H2O2), hydroxyl radical (⋅OH), nitric oxide (⋅NO), peroxynitrite
chondrial copper bioavailability through: (1) direct delivery of copper
(ONOO− ), and lipid peroxides (LPO), are continuously produced during
ions or ionophores [64,65], (2) inhibition of copper efflux transporters
electron transfer reactions in aerobic metabolism. Under physiological
(ATP7A/ATP7B) [66,67], and (3) depletion of GSH, a key copper
conditions, ROS levels are tightly regulated by antioxidants such as su­
chelator [68,69]. However, intrinsic barriers—including the Warburg
peroxide dismutase (SOD), catalase, glutathione (GSH), peroxidases,
effect-mediated suppression of mitochondrial respiration and hetero­
and vitamins to maintain redox homeostasis. However, during heat
geneous expression of cuproptosis regulators like ferredoxin 1 (FDX1)
stress [54], intracellular oxygen levels rise due to xanthine oxidase
and lipoylated proteins—limit therapeutic efficacy across cancer types
activation and mitochondrial electron transport chain (ETC) activity
(Fig. 4) [70].
[55], leading to excessive ROS accumulation. This oxidative surge
The interplay between HT and cuproptosis remains underexplored.
damages cellular components and activates multiple cell death path­
While HT modulates mitochondrial oxidative phosphorylation
ways. Notably, heat stress downregulates SOD1 (CuZnSOD) expression
(OXPHOS), a process linked to copper sensitivity, its effects vary by
and activity, amplifying ROS production [56]. Uncontrolled ROS and
cancer lineage. In ovarian and uterine cancers, HT reduces glycolysis
reactive nitrogen species (RNS) initiate free radical chain reactions that
while enhancing OXPHOS to sustain ATP production, whereas colorectal
oxidize proteins, lipids, polysaccharides, and DNA, with mitochondria
cancer exhibits increased glycolysis and spare respiratory capacity
being both the primary ROS source and target. Mitochondrial antioxi­
under thermal stress [71]. Notably, HT-driven OXPHOS amplification
dant failure destabilizes free radical equilibrium, impairing ETC func­
sensitizes tumors to cuproptosis, as demonstrated by Lin et al. [72], who
tion, ATP synthesis, respiration coupling, and structural integrity of
engineered a thermoresponsive nanomedicine (DIE) co-encapsulating
biomolecules. Consequently, mitochondrial dysfunction disrupts
indocyanine green (ICG) and elesclomol (ES) within disulfide-rich
cellular homeostasis, accelerating cell death (Fig. 4).
dextran copolymers. Near-infrared (NIR) laser activation of DIE
While heat-induced oxidative damage affects both normal and ma­
reduced GSH levels, elevated cytotoxic Cu2+ concentrations, and
lignant cells, cancer cells often resist apoptosis, driving therapeutic in­
amplified FDX1-mediated lipoylated protein aggregation, thereby
terest in non-apoptotic programmed cell death (PCD) mechanisms.
potentiating cuproptosis in melanoma (Fig. 5). This approach synergized
Identified non-apoptotic PCD pathways include necroptosis, autophagy,
with PD-L1 checkpoint blockade to suppress tumor growth and metas­
ferroptosis, pyroptosis, and cuproptosis. NPs further enhance thera­
tasis via immunogenic cell death.
peutic synergy by augmenting chemo-/radio-/immune-/HT-mediated
Although MHT itself does not directly regulate the cuproptosis
PCD induction. NPs themselves can trigger apoptotic and non-apoptotic
pathway, as research clarifies the role of HT (a downstream effect of
death, diversifying treatment modalities. In summary, heat stress exac­
MHT) in inducing cuproptosis, integrated strategies combining thermal
erbates oxidative damage, activating intrinsic apoptotic and alternative
modulation, copper biology, and immunotherapy are emerging as
PCD pathways. Elucidating ROS dynamics and their cellular impacts is
transformative tools in oncology.
pivotal for designing targeted therapies that selectively eliminate cancer
cells while preserving normal tissue [57].
3.6. HT promotes ferroptosis of tumor cells

3.4. HT promotes necroptosis of tumor cells HT synergistically induces ferroptosis in tumor cells by regulating
iron metabolism and redox balance, with its underlying mechanisms
Necroptosis is defined as a novel cell death that has some dis­ closely tied to the microenvironment-responsive properties of iron-
tinguishing features compared to other cell death types. The primary containing nanomaterials. This primarily involves iron ion release trig­
causes of necroptosis are widely recognized to be the pharmacological gered by acidic microenvironments and activation of the Fenton reac­
blocking or genetic removal of caspases, which, when cells are unable to tion [73].
initiate apoptosis, can serve as an alternative "safety net" within the Iron-based nanomaterials (e.g., Fe3O4 mesocrystals, iron MOFs) un­
spectrum of PCD [58]. And targeting necroptotic cell death in cancer dergo structural dissociation and release free iron (Fe2+/Fe3+) under the
cells has potential therapeutic benefits. Necroptosis, distinct from acidic conditions (pH 6.5–6.9) of the TME or the low-pH environment
apoptosis, constitutes an inflammatory type of PCD. The inflammation (pH 4.5–5.5) of lysosomes. HT further accelerates this process: localized
triggered by necroptosis has the potential to enhance immune-mediated temperature elevation enhances the degradation kinetics of nano­
mechanisms against cancer [59]. There are different pathways by which materials, promoting greater accumulation of iron ions in the cytoplasm.
NPs trigger necrosis in cells (Fig. 4). The predominant mechanism in Released iron ions drive ferroptosis through two main pathways: 1.
necrotic cell death is the pro-oxidant pathway, which involves the Amplified oxidative damage via the Fenton reaction: Fe2+ directly par­
production of ROS. This can result in a decrease in mitochondrial ticipates in the classical Fenton reaction with H2O2 to generate ⋅OH:
membrane potential and DNA damage, ultimately steering the cell to­ Fe2++H2O2→Fe3++OH− +⋅OH. ⋅OH is one of the most potent ROS spe­
wards a necrotic demise [60]. Additionally, another pathway by which cies (oxidation potential 2.8 V), capable of directly attacking poly­
NPs induce necrosis involves the disruption of lysosomal structure due unsaturated fatty acids in cell membrane phospholipids to initiate a lipid
to the rapid lysosomotropic degradation of NPs, leading to the release of peroxidation chain reaction and form phospholipid hydroperoxides
toxic contents into the cytosol and culminating in necrotic cell death (Fig. 4) [74]. Fe3+, the primary form of iron in circulation, binds to
[57]. transferrin (TF). It is transported into cells with the help of the

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Fig. 5. Thermal stimulation boosts ES-induced cuproptosis via increased FDX1 expression and mitochondrial respiration. Reproduced with permission [72].
Copyright 2025, Wiley.

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membrane protein transferrin receptor 1 (TFR1) and localized in 4. Mechanism of MHT

endosomes [75]. In endosomes, Fe3+ is reduced to Fe2+ by
six-transmembrane epithelial antigen of the prostate 3 (STEAP3). The HT involves localized or systemic temperature elevation, with clin­
endocytosed Fe2+ is then released into the cytoplasm via solute carrier ical applications favoring tumor-specific targeting. Current non-
family 11 member 2 (SLC11A2), forming a labile iron pool (LIP) that nanoparticle-based local HT methods often prove ineffective due to
catalyzes hydroxyl radical production and triggers ferroptosis [74,76]. poor temperature uniformity and insufficient deep-tissue penetration
2. Mitochondrial dysfunction: Iron ions induce ROS bursts in the mito­ [84], limiting their oncological utility. Advances in nanotechnology
chondrial matrix, disrupting mitochondrial membrane potential and have improved the precision and safety of localized HT, particularly
inhibiting electron transport chain activity. This leads to a synergistic through MNPs engineered for tumor-selective heat generation.
collapse of energy metabolism and exacerbation of membrane lipid The heat generation mechanism of magnetic materials primarily
peroxidation. relies on nanoscale relaxation processes and hysteresis losses, as sys­
Unlike other forms of programmed cell death (e.g., apoptosis), fer­ tematically described by Rosensweig in his seminal work on MFs heating
roptosis is characterized by mitochondrial structural abnormalities (e.g., under AMF [85]. For NPs <15 nm, eddy current heating is negligible,
increased membrane density) rather than nuclear shrinkage or plasma and the dominant mechanisms are:1. Hysteresis Loss: In ferromagnetic
membrane rupture. While ferroptosis is associated with elevated iron materials, magnetic domains (Weiss domains) generate heat during
levels and can be inhibited by iron chelators, it is not unique in this AMF-induced reorientation, as the magnetization curve forms a hys­
regard—apoptosis and necrosis also correlate with high iron levels and teresis loop representing energy dissipation. This is characterized by
exhibit similar sensitivity to iron chelation [77]. Current evidence at parameters such as magnetization saturation (Ms), retentivity (Mr), and
least partially confirms the iron-dependent nature of ferroptosis. coercivity (Hc) (Fig. 6A). 2. Relaxation Mechanisms: (1) Néel Relaxa­
tion: Occurs in superparamagnetic NPs, where the magnetic moment
reorients within the crystal lattice against magnetocrystalline anisot­
3.7. HT promotes pyroptosis of tumor cells ropy energy, requiring thermal activation. The relaxation time depends
on particle volume and anisotropy constant. (2) Brownian Relaxation:
Pyroptosis, a form of PCD, is characterized by gasdermin-mediated Arises from particle rotation in the fluid medium, governed by the hy­
membrane permeabilization. This process is typically initiated by drodynamic volume and viscosity. In real systems, smaller particles are
inflammasome activation in compromised cells and proceeds via two dominated by Néel relaxation and larger ones by Brownian relaxation.
primary pathways: (1) caspase-1/4/5/11-mediated cleavage of gasder­ In the case of ferromagnetic NPs, a phenomenon called super­
min D (GSDMD), and (2) caspase-3-dependent activation of gasdermin E paramagnetism occurs. The hysteresis loop of superparamagnetic NPs is
(GSDME) (Fig. 4) [78–80]. Emerging evidence suggests that additional fundamentally characterized by zero Mr, zero Hc, central symmetry, and
gasdermin family members, including GSDMA, GSDMB, and GSDMC, a linear or weakly non-linear magnetization curve (Fig. 6B). This serves
participate in pyroptosis induction via their conserved pore-forming as a direct manifestation of the thermal fluctuation-dominated magnetic
domains. Upon proteolytic cleavage, the N-terminal domain of gasder­ moment behavior at the nanoscale, highlighting the unique magnetic
mins oligomerizes and integrates into plasma membranes, forming pores properties arising from size-dependent effects in nanomaterials. Their
that disrupt osmotic homeostasis and culminate in cell lysis [81]. heat generation efficiency is quantified by the SAR, and its formula is
Notably, preclinical studies demonstrate that pyroptosis induction in SAR = μ0⋅π⋅χ′′⋅f⋅H20⋅ρ− 1,where χ′′ is the imaginary component of mag­
<15 % of tumor cells can achieve complete tumor regression in vivo, netic susceptibility (loss factor), f is AMF frequency, H0 is magnetic field
highlighting its therapeutic potential [82]. amplitude, and ρ is particle density. This model highlights the critical
By clarifying this mechanism, the MNP-mediated tumor cell death role of NP size, AMF parameters, and magnetic properties in optimizing
can be further optimized. Liu et al. engineered EpCAM-targeted mag­ heat output. Beyond classical mechanisms, Rinaldi et al. proposed
netic polymer nanoparticles co-loaded with glucose oxidase, paclitaxel, magnetically mediated energy delivery (MagMED), a nanoscale thermal
and ASC/CARD plasmids to synergistically induce pyroptosis, metabolic effect driven by spin-lattice interactions in high-frequency AMFs. Unlike
starvation, and chemotherapy [83]. Elevated caspase-1, cleaved inter­ bulk heating, MagMED enables precise energy deposition at the cellular
leukin-1β (IL-1β), and GSDMD levels demonstrated inflammasome level, influenced by particle surface effects and collective behavior in
activation and pyroptotic pathway initiation. Collectively, MNP-based clusters.
systems represent a multimodal therapeutic strategy, combining
pyroptosis induction, nutrient deprivation, and cytotoxic drug delivery
to establish a robust anticancer paradigm.

Fig. 6. Schematic drawing of (A) a hysteresis loop of a ferromagnetic material and (B) typical plot of a superparamagnetic material. Reproduced with permission [7].
Copyright 2020, Wiley.

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5. Advantages of MHT compared with other types of HT these systems permits a unified theragnostic approach, blending di­
agnostics and therapy [75,86]. Additionally, static AMF can trigger the
The utility of MF is based on their unique responsive nature. This release of therapeutic agents, nucleic acids, and antioxidant enzymes
encompasses the use of magnetic guidance under a static AMF, the in­ [87]. MNPs in an oscillating or AMF generate heat due to hysteresis loss
crease in temperature under an oscillating AMF, or a combination of and/or Néel relaxation, which is widely used for targeted heating and
both in alternating applications. These methods can effectively treat controlled drug release within tumors [88,89]. The thermal bystander
deeply located diseases, penetrating biological barriers such as tissues, effect ensures that the injected MF is evenly distributed for uniform
bones, or blood vessels without obstruction, thanks to the high pene­ heating and expanded coverage. In complex tumor tissues, precise
tration capability of AMF. Furthermore, the integration of MRI within control over the distribution and heating range of the MF is achievable

Table 2
This table summarizes the main advantages and disadvantages of different current hyperthermia treatments, tissue penetration depth, thresholds and clinical
application status.
Type Heat technology Major advantages Major disadvantages Tissue Threshold Clinic application Reference
penetration level
depth

Magnetic Alternating • Non-invasive • Side effects and toxicity Unlimited 7Tesla Still in the pre-clinical [251–253]
hyperthermia magnetic field • Easy accumulation of induced by particle research stage
magnetic particles accumulation Currently, only
• Spatiotemporal control • High cost Germany approved the
• Insensitive to the • Complexity use of MHT as an
surrounding medium • Large facilities adjuvant therapy with
• Hot bystander effect • Limited information of RT
• Curie temperature MIONP distribution in
• Intracellular tissue
hyperthermia • Limited and invasive
• No penetration depth thermometry
limit
• Repeated treatment
• Treatment of brain
tumors through the
blood-brain barrier
2
Photothermal Near-infrared (NIR) • Low cost • Limited invasive for the 3 cm 10J⋅cm− PTT agents have not [254,255]
therapy(PTT) laser • Easily tuned deep zone tissue yet been tested in large
photoabsorbers、 • High specificity penetration clinical trials; laser
NIR • Microinvasive • Harmful UV ablation without PTT
• Accurate space-time • Inconsistent responses agents has been used
selectivity to light clinically
• Low adverse reactions to
normal tissues
Microwave Probes that make • The highest rate of bulk • Frequent pain and 3–7 cm 915 MHz Commonly used [256]
hyperthermia energy from tissue heating discomfort clinical hyperthermia
microwaves • Relatively unaffected by • Heat dose and technology
tissue charring positioning is difficult Examples:superficial
• The ability to create to accurately and deep tumors、
ablations that can cover • Heating of normal chronic strain of soft
most tumors up to 5 cm tissue tissue bones and joints
in diameterin the • Blood perfusion and
shortest amount of time vascular heat sink
(typically 4–10 min) • Electromagnetic and
thermal
inhomogeneities in and
around the tumor
Radiofrequency Radio wave • Microinvasive • Eschar or dry tissue 5 cm 2.45 GHz The most commonly [257]
ablation • Partially curative effect affects the current used clinical
on some diseases (such conduction so that the hyperthermia
as liver tumors less than scope of action is less technology
5 cm in diameter) than microwave Examples: early liver
• Multiple treatment can ablation cancer、early non-
be repeated • Positioning means still small cell lung cancer
need to be optimized benign thyroid tumors
• Tissue damage risk
• Uncomfortable for
patients
Ultrasound Ultrasound ⋅ High penetration depth ⋅ Hard to achieve 10–15 cm Exposure The clinical [258–263]
hyperthermia ⋅ Easy to adjust homogeneous exposure Intensity: 100 time: transformation of
⋅ Spatiotemporal control within large zones mW cm− 2 10min ultrasound-mediated
⋅ Low cost • High reflection at air (Diagnosis); nanomedicines
⋅ Capability of focused and bone interface 3W⋅cm− 2 remains to be fully
heating • High absorption in bone (Therapy) studied
⋅ Integrating diagnostic Mechanical
imaging with index: 0.3
therapeutic function
• Non-invasiveness and
safety

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

through multi-point injection, selectively targeting tumors while sparing through ROS generation, position ultrasound as a multifunctional
normal tissues. The MF’s Curie temperature property allows for auto­ therapeutic platform.
matic temperature control and maintenance, which is crucial for deep
tumor thermotherapy. These features set magnetic thermotherapy apart 6. Magnetothermal related materials
from other thermal treatments. However, its application is typically
limited to accessible tumor nodules and not suitable for metastatic or The magnetothermal performance of MNPs is critically determined
disseminated tumors. The use of magnetic guidance is complex, by their structural morphology (size, shape, crystallinity) and surface
requiring precisely focused and tissue-penetrating external AMF. modifications (coatings, functionalization). Smaller NPs (<50 nm)
Real-time accurate temperature measurement of the target HT tissue exhibit enhanced tumor penetration and renal clearance efficiency,
remains a technical challenge [88]. Current research focuses on opti­ while larger particles (>100 nm) can be more advantageous in targeting
mizing magnetic and irradiation technologies. We summarize the pros the tumor associated macrophages (TAMs) in certain applications [98].
and cons of magnetic heating versus other thermal therapies and their Regarding shape, non-spherical architectures (e.g., rods, cubes, plates,
clinical applications in Table 2. and needles) exhibit distinct magnetic properties compared to spherical
PTT is an emerging cancer treatment modality that utilizes near- particles due to anisotropic demagnetizing factors, which influence
infrared (NIR) laser-absorbing agents to selectively destroy malignant magnetic moment relaxation dynamics and hysteresis losses. For
cells through localized hyperthermia upon NIR irradiation [90]. PTT example, rod-shaped MNPs with high aspect ratios show enhanced
shows potential for eradicating primary tumors and locoregional lymph magnetic anisotropy, leading to higher hysteresis losses and signifi­
node metastases, effectively addressing early-stage metastatic progres­ cantly increased SAR values. Cube-shaped particles, with their sharp
sion. Furthermore, it exhibits synergistic potential with systemic ther­ edges and corners, can further modulate magnetic dipole-dipole in­
apies for managing disseminated metastases [91]. However, critical teractions between particles, potentially inducing collective magnetic
challenges persist, such as incomplete ablation of thermotolerant cells in behaviors that enhance heat generation under AMF. Conversely,
deep-seated metastases and the necessity to maintain intratumoral spherical MNPs offer superior colloidal stability and reduced nonspecific
temperatures above 50 ◦ C for optimal efficacy [92]. Tissue attenuation cell uptake due to their symmetrical geometry, making them favorable
of NIR wavelengths limits penetration depth, often requiring increased for systemic circulation and tumor accumulation via the EPR effect.
laser intensity or prolonged exposure, which risks collateral thermal Surface engineering with polymers (e.g., PEG, chitosan) or inorganic
damage to adjacent healthy tissues. Current research prioritizes nano­ shells (e.g., silica, gold) improves colloidal stability, reduces immune
particle engineering and dosimetry optimization to enhance therapeutic recognition, and prolongs circulation half-life. For instance, PEG can
specificity. reduce the overall adsorption of plasma proteins and prevent the ag­
Thermal ablation techniques, particularly radiofrequency ablation gregation of MNP, thereby helping MNP escape from mononuclear
(RFA) and microwave ablation (MWA), constitute mainstream clinical phagocyte system (MPS). Moreover, studies have found that as the
interventions. These modalities achieve cytotoxic temperatures molecular weight of PEG increases from several thousand to several
exceeding 50 ◦ C, serving as either standalone therapies or adjuvants to hundred thousand, the circulation time of MNP in the blood can be
conventional treatments. MWA operates at high power (typically 4–10 extended from 30 min to 24 h [98]. Crystalline anisotropy and defect
min), enabling rapid volumetric heating less impeded by tissue desic­ density directly govern magnetic susceptibility and SAR, with
cation and capable of ablating lesions ≤5 cm with margins [138]. single-domain superparamagnetic NPs demonstrating optimal heating
Clinical trials demonstrate MWA’s efficacy across diverse anatomical efficiency under AMF [99].
sites, including bone, pancreas, and prostate. Nevertheless, technical The metabolic pathways of MNPs depend on size and surface prop­
limitations persist inconsistent thermal dosing due to antenna design erties: renal clearance (<15 nm particles), hepatobiliary excretion, or
constraints, procedural discomfort, and heat sink effects from vascular MPS uptake. Compared to earlier nanomaterials, advancements in
structures. Although early innovations advanced interstitial ablation nanoengineering have significantly enhanced the metabolic profiles and
protocols, the complexity of achieving homogeneous tumor heating has biosafety of MNPs. Traditional inorganic MNPs (e.g., SPIONs) faced
restricted MWA’s oncological applications. challenges such as hepatic/splenic accumulation, iron ion leakage-
RFA remains the gold standard for solid tumor ablation, employing induced oxidative stress, and long-term retention risks. Modern sur­
high-frequency alternating currents (350–500 kHz) to induce ionic face engineering strategies—including PEGylation, zwitterionic coat­
friction and thermal coagulation (60–120 ◦ C) [93]. The ablated volume ings, and biodegradable polymer encapsulation (e.g., PLGA, dextran)—
depends on both local joule heating and convective cooling from blood enable controlled biodegradation and improved renal clearance.
flow. Following FDA approval for lung tumors (2007) and NCCN The nanosystems currently reported for MHT biomedicine can be
guideline inclusion (2009), RFA gained recognition as a minimally generally classified into three categories: inorganic, organic, and
invasive alternative to resection for lesions <5 cm, particularly in pa­ organic-inorganic hybrid micro-/nanoplatforms. The disciplines of ma­
tients with comorbidities contraindicating surgery [94]. Advantages terials engineering and synthetic chemistry exhibit distinct differences,
include percutaneous applicability under local anesthesia, repeatability which in turn lead to varied biomedical applications of these multi­
for multifocal/recurrent tumors, and reduced iatrogenic seeding risk. functional NPs (Fig. 7).
However, RFA efficacy diminishes in highly desiccated tissues compared
to MWA, and procedural pain remains a patient concern.
Ultrasound-based therapies address penetration limitations of 6.1. Inorganic nanomaterials
external beam modalities while avoiding ionizing radiation. Adjustable
parameters (frequency, duty cycle, duration) enable depth-specific en­ MNPs are essential counterparts of magnetic nanocomposites. They
ergy deposition (up to tens of centimeters) with minimal off-target ef­ can be classified into magnetic alloy NPs (eg iron, nickel, and cobalt) and
fects [95]. High-intensity focused ultrasound (HIFU) achieves thermal magnetic metal oxide NPs (eg iron oxides, nickel oxide, and lanthanum
ablation, whereas pulsed protocols facilitate mechanical tissue frac­ strontium manganite). Table 3 encapsulates a review of the primary pros
tionation. Low-intensity ultrasound combined with microbubbles en­ and cons associated with various commonly employed inorganic mate­
hances drug delivery via cavitation-mediated vascular permeability rials in MHT [100].
[96]. Emerging strategies employ sonosensitizers activated by ultra­
sound to induce localized sonochemical cytotoxicity, forming the basis 6.1.1. Monocomponent MNPs
of sonodynamic therapy (SDT) [97]. These multifunctional applications,
including diagnostics, targeted drug release, and tumor eradication 6.1.1.1. Fe, Ni, Co-based MNPs. Iron nanoparticles (FeNPs) exhibit

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 7. Schematic diagram of several classic and latest magnetothermal related materials introduced in this article.

good physical and chemical stability, less expensive, and environmen­ easy scale-up and high activity. However, although single-atom NPs
tally safe. In prior studies, iron carbonyl [Fe(CO)5] was decomposed in have broad application prospects in many fields, there are still many
the presence of oleic acid to yield mono-dispersed FeNPs [101]. challenges. One is that the methods and techniques for obtaining higher
Considering the susceptibility of iron NPs to oxidation, a straightforward purity and controllable single-component NPs are not mature enough
aqueous-phase synthesis was employed, utilizing poly and need to be further improved. In addition, the stability of single-atom
(N-vinylpyrrolidone) (PVP) to confer antioxidation properties to the NPs is also an important issue. Due to the high surface energy and sol­
metal surface [102]. Nickel (Ni) NPs with uniform size distribution were ubility of single-atom particles, they are often prone to aggregation and
synthesized by reducing Ni(acac)3 in the presence of hexadecylamine loss of activity in biological applications. Therefore, researchers are
(HDA), resulting in an average particle size of 3.7 nm [103]. Cobalt (Co) developing some methods to enhance the stability of single-atom NPs,
NPs with a size of approximately 26 nm were produced using a bulky such as surface modification and coating to reduce their interaction with
trialkyl phosphine as a reducing agent, whereas larger NPs, with sizes up the external environment.
to 71-11 nm, were formed in the presence of a less bulky trialkyl
phosphine, demonstrating the role of trialkyl phosphine as a coordi­ 6.1.1.2. Superparamagnetic gold-nanoparticles (SPAuNPs). Beyond the
nating surfactant interacting with the neutral metal surface sites [104]. aforementioned single-component magnetic nanostructures, there have
Including but not limited to the above single component, NPs have many been reports in recent years of a novel cancer diagnostic agent that
unique properties and applications. Due to its small size and high spe­ harnesses the gold-magnetic effect. SPAuNPs, have been developed by
cific surface area with organisms, it can be used as an efficient catalyst to synthesizing them on a viral capsid particle engineered to target tumor
accelerate the chemical reaction rate. Compared with natural enzymes, cell receptors (TCR). This innovation addresses the limitations
nanozymes have obvious advantages such as low cost, high stability, commonly associated with other NPs. For instance, SPIONs are hindered

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Table 3 synthesized by reducing Pt(acac)2 and decomposing Fe(Co)5 in octyl

Comparison of the main advantages and disadvantages of various commonly ether solvent. The gold coating enhances the biocompatibility of these
used inorganic materials in MHT. NPs [113]. Furthermore, other binary metallic alloys like Fe12Co88,
MHT material Major advantages Major disadvantages Reference Fe40Co60, and Fe60Co40, which exhibit superior magnetic properties, are
Monocomponent ⋅ Small size and ⋅ Methods and [264]
also known. Encapsulating these alloys with materials such as gold,
magnetic high specific techniques for higher silver, or a graphitic layer helps inhibit oxidation. Metallic alloys such as
nanoparticles surface area. purity are not Fe-Pt and Ni-Si have attracted significant interest due to their adjustable
Examples:Fe, Ni, ⋅ As nanozymes: mature. Curie temperatures, which can be tailored to meet specific requirements
Co-based low cost、 high ⋅ Poor stability: prone
[114]. Despite the immense potential of metallic alloys in various ap­
magnetic stability、easy to aggregation and
nanoparticles scale-up and loss of activity. plications, they do face challenges related to corrosion, bio-inert nature,
high activity. and instability within the human body. These limitations restrict their
Metallic alloys ⋅ Controlled ⋅ Corrosion. [115] use in HT for cancer. Nevertheless, metallic alloys continue to be
nanoparticles temperature in ⋅ Bioinert nature. extensively utilized as biomaterials in diverse applications [115].
Examples: Fe–Pt, AMF. ⋅ Biocompatibility
Ni–Si, Ni–Cu ⋅ Optimal Curie issues.
temperature. ⋅ Instability at 6.1.3. Metal oxide-based nanomaterials
application site.
Metal oxide-based ⋅ Good thermal ⋅ Agglomeration of [265] 6.1.3.1. Unmodified metal oxides. The utilization of iron oxide, rather
nanomaterials conductivity and nanoparticles during
than traditional metals or alloys, has proven to be highly effective in
Examples: viscosity. AMF application.
SPIONS, silica- ⋅ No remanence of ⋅ Colloidal instability. various applications. Among the different magnetic oxides, iron oxide
coated Fe3O4 magnetism after ⋅ Dissolution of stands out as the most studied and widely used compound, showcasing
HAp-coated-iron removal of SPIONs and possible impressive magnetic properties while also being biocompatible.
oxide external AMF. release of iron which
Magnetite, a form of iron oxide, has emerged as a powerful mineral with
nanoparticles ⋅ Effective drug can promote cancer
delivery. growth. a myriad of applications due to its superior magnetic strength (Table 4).
⋅ Can be exploited ⋅ Lower magnetic The composition and size of magnetite significantly influence its mag­
for simultaneous characteristics as netic properties, with particles below 20 nm becoming super­
MRI、 drug compared to bulk paramagnetic, termed as SPIONs. The superparamagnetic nature of
delivery、 and materials.
SPIONs, coupled with their biocompatibility, has resulted in their
HT.
widespread use in biomedical applications. The unique thermal con­
ductivity and viscosity of Fe3O4 nanofluid further enhance its suitability
by their toxicity when used for in vivo MRI. This is due to ROS causing for MHT applications. Moreover, SPIONs serve as effective contrast
damage to DNA and proteins, as well as triggering inflammatory re­ agents for MRI imaging and can be precisely directed to target sites
sponses [105–107]. Additionally, the limited tissue penetration of through external AMF [116]. SPIONs have emerged as a promising tool
near-infrared lasers further complicates their functionality. Gold nano­ in anti-cancer therapies, offering unique advantages such as zero coer­
particles (AuNPs) larger than 8 nm face obstacles passing through the civity and remanence. These properties ensure that SPIONs do not retain
kidney’s filtration system, resulting in their accumulation in various residual magnetic interactions after exposure to external AMF, making
cells, tissues, and organs, particularly in the liver. This accumulation can them ideal for medical applications where precise control over magnetic
lead to acute inflammation, tissue apoptosis, and an uncontrolled in­ properties is essential. The versatility and remarkable properties of iron
crease in Kupffer cells [108]. However, SPAuNPs, with diameters less oxide-based materials, particularly SPIONs, have paved the way for
than 3 nm, are efficiently cleared through the kidneys, reducing the risk significant advancements in various fields, ranging from healthcare to
of toxicity by minimizing their retention time in vivo. Studies on mice technology, highlighting their potential for future innovations. Despite
have shown that treatment with small AuNPs does not significantly the potential benefits of SPIONs in cancer treatment, several challenges
impact the number of Kupffer cells in the liver, highlighting the potential must be addressed to fully exploit their capabilities. One major concern
of SPAuNPs in minimizing harmful effects. is the dissolution of SPIONs, which can result in the release of iron
particles in the body, potentially promoting tumor growth. In addition,
6.1.2. Metal alloys MNPs SPIONs are prone to agglomeration when subjected to alternating fields
Metal alloy NPs have emerged as a highly promising area of research due to their high surface energy and attractive magnetic and van der
due to their super magnetic properties [109]. Among the most notable Waals forces [117].
examples are Iron-Platinum (FePt) and Iron-Palladium (FePd) nano­ To tackle these issues, researchers have explored coating SPIONs
structures, which are renowned for their exceptional chemical stability with biocompatible substances like silica, small organic molecules, and
and magnetic crystallinity [110]. FePt NPs have shown great potential in hydroxyapatite [118–120]. Although these coatings can help reduce the
the field of biomedicine, being synthesized through solution-phase release of iron species and mitigate dipole interactions, they have shown
methods or vacuum deposition. In the case of FePd NPs, they have limited success. Thick coatings may eliminate dipole interactions but
been successfully prepared using adamantine carboxylic acid and can also destabilize the colloidal solution of SPIONs. Moreover, SPIONs
tributyl phosphine as stabilizers at room temperature via the organic exhibit insufficient thermal conversion efficiency due to their degraded
phase thermal decomposition method. These FePd NPs exhibit remark­ magnetic susceptibility, with different magnetic parameters observed
able super magnetic properties with a tunable size ranging from 11 to 16 depending on the form of iron oxide. For instance, magnetite has a
nm. Previous studies have utilized a wet-chemical approach to produce higher magnetic saturation than maghemite, emphasizing the impor­
monodisperse FePd NPs with a face-centered cubic (fcc) structure, tance of understanding these properties to optimize the effectiveness of
achieved by reducing Pt(acac)2 and decomposing Fe(Co)5 [111]. How­ SPIONs in anti-cancer therapies. In conclusion, while SPIONs hold great
ever, a transformation to a face-centered tetragonal (fct) structure can promise in cancer treatment, addressing challenges such as dissolution,
lead to aggregation issues. To address this problem, thermal annealing agglomeration, and thermal conversion efficiency is crucial for maxi­
has been employed to convert fcc-structured Fe3O4 NPs coated with mizing their therapeutic potential. Thorough research and careful
magnesium into fct-structured FePt NPs [112], with the layer of mag­ consideration of these factors are essential to overcome these obstacles
nesium oxide (MgO) serving to prevent aggregation. In another inter­ and fully leverage the benefits of SPIONs in anti-cancer therapies.
esting development, FePt NPs with a gold coating have been successfully

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Table 4
Summary of some ferrite materials in recent years.
NPs type Size Cancer cell Injection Injection AMF SAR Maximum Results Year Reference
(nm) line dose route strengths temperature

Iron oxide NPs 18 4T1 50 μL of 0.5 Intratumoral – – 43 ◦ C The improved targeting and 2019 [266]
(IOs) mg kg− 1 delivery uniformity enables
more effective MHT cancer
ablation than otherwise
identical, nontargeting IOs.
Co–Fe NPs 17 A431 50 μL 14 mg Intratumoral 105 kHz,20 400 Wg- – Complete tumor regression 2020 [96]
±2 mL− 1 kAm− 1 1
and improved overall
survival in an in vivo
murine xenograft model.
1
Zn0.4Mg0.6Fe2O4 28 L929 6 mg mL− In vitro cells – – 46 ◦ C Ensuring the 2021 [267]
implementation of OA-
coated Zn-Mg Ferrite
nanoparticles with
minimum dose rate.
FVIO 73.9 H22 1 mg of Intratumoral 365 2300Wg- 44.1–44.3 ◦ C FVIO-mediated MH and 2024 [268]
Fe⋅cm− 3 kHz,300 Oe 1
Sorafenib offer sastrategy
for HCC treatment by
promoting accelerated
ferroptosis.
1
CuFe2O4 200 4T1 1.5 mg mL− Intratumoral 577 – 45 ◦ C Magnetic mesoporous 2022 [269]
kHz,3700 W CuFe2O4 NPs with excellent
magnetothermal conversion
ability and large mesopores
enables them as an excellent
MHT agent and a good drug
carrier.
CoFe2O4 12 CT26 106.2–3000 Intratumoral 261 400 Wg- 46–48 ◦ C Provides more efficient 2021 [270]
±4 mg kg− 1 kHz,15–25 1
heating while achieving
mT greater biosafety.
1
Fe3O4 PLGA 172 CT26 25 mg kg− Intratumoral 293 kHz, – 44 ◦ C MHT + chemotherapy 2018 [191]
doxorubicin 12.57 presented marked tumor
kAm− 1 growth suppression
compared to MHT and
chemotherapy alone.
1
Fe-Fe3O4 PECc 33 U87MC 40 mg kg− Intravenous 13.56 – 38◦ C-water On the day 15 post-MHT the 2018 [271]
(RGDyK) glioblastoma kHz,40 relative tumor size volume
peptide kAm− 1 reduced by half.
Hematoxylin-eosin staining
revealed nuclear
fragmentation and
shrinkage.
1
Fe3O4 NGO- 36.8 C6 glioma 2 mg kg− Intravenous 242.5 – 65◦ C- MRI and Prussian blue 2018 [272]
PLGA IUdR kHz,21.8 medium staining revealed the higher
kAm− 1 localization of NPs in tumor
under AMF.

6.1.3.2. Surface-engineered metal oxides. Sood and his team have made common practice in the field of nanomedicine, particularly for HT ap­
significant strides in the production of Fe3O4/Au core-shell nano­ plications. This method not only improves the stability and biocom­
composites through a novel method involving the integration of gold patibility of the NPs but also serves as a versatile platform for further
chloride and trisodium citrate dihydrate into a suspension of existing modifications to enhance targeting specificity. The advantages of silica,
Fe3O4 NPs, which were then gently heated during their study [121]. The such as biocompatibility, stability, non-toxicity, and compatibility with
addition of the gold shell served a dual purpose by shielding the core various functional groups, have been widely recognized in the scientific
from corrosion while displaying excellent biocompatibility and binding community [124]. Silica coating plays a crucial role in forming a pro­
capabilities through amine/thiol terminal functionalities [122]. These tective shield around the iron oxide core of the NPs, preventing direct
nanocomposites, derived from pre-synthesized magnetite NPs, demon­ contact with the external environment. This protective barrier helps
strated remarkable potential in biosensing applications, especially in prevent agglomeration and reduces the potential toxicity associated
protein detection and disease diagnosis. Moreover, the incorporation of with the NPs, making them safer for use in medical applications. Re­
gold nanoshells was found to significantly enhance photodegradation searchers, like Madhappan Santha Moorthy and their team [125], have
efficiency under UV light, allowing for photodegradation even under successfully synthesized Fe3O4@SiO2 NPs for HT applications in cancer
natural sunlight due to gold’s responsiveness to visible light [123]. treatment. In their study, they encapsulated FeNPs with silica to prevent
Tamer and his research team also made significant contributions to this aggregation in suspensions and to allow for the attachment of biological
area by developing anisotropic core-shell nanocomposites using molecules for targeted therapy. This innovative approach combines
Fe3O4@Au NPs dispersed in sodium citrate before introducing them into chemotherapy and thermal therapy to effectively target cancer cells,
a growth solution comprising cetyl trimethylammonium bromide, showcasing the promising potential of silica-coated IONPs in advancing
HAuCl4, AgNO3, and ascorbic acid at room temperature. The resulting medical treatments. The ability of silica coating to enhance the thera­
high surface area of the product greatly improved its ability to detect peutic efficacy of IONPs while minimizing potential risks highlights the
Escherichia coli in large quantities, showcasing the potential of these significance of this technique in the field of nanomedicine.
nanocomposites in a wide range of applications.
The use of silica-coated IONPs followed by functionalization is a 6.1.3.3. Binary ferrite. Pure magnetic metals such as Cobalt, Iron, or

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Cobalt Iron have high saturation magnetization values but are prone to polyol method in ethylene glycol, MnFe2O4 NPs achieve Ms of 90–95
high losses and toxicity. Additionally, they are sensitive to oxidation, emu⋅g − 1 at 4 K, yielding SAR up to 1200 Wg-1 (Fe + Mn basis). Align­
making them unsuitable for biomedical applications without a safe ment in a uniform static AMF followed by matrix immobilization en­
biocompatible coating. An alternative option is the use of ferrites, which hances heating efficiency by 40–60 % compared to dispersed NPs [128].
can be created by substituting various metal ions like Nickel, Cobalt, and Notably, MnFe2O4 demonstrates lower cytotoxicity than zinc ferrite,
Manganese for Fe2+ ions in the magnetite lattice. Among these ferrites, with 50 % cell viability observed at 0.2 mg mL− 1 after 24-h exposure
cobalt ferrite stands out with 90 % of the saturation magnetization of [128].
magnetite but possesses significantly higher magnetic anisotropy and Particle size critically governs HT efficacy: NPs >15 nm exhibit
coercivity. This results in a larger area for magnetic hysteresis, indi­ higher Ms (~80 emu⋅g− 1) and SAR values (H0 = 18 kAm− 1, f = 336 kHz),
cating that cobalt ferrite NPs require more intense AMF for effective while sub-10 nm particles show diminished heating due to suppressed
utilization compared to other spinel NPs of similar size. These findings Néel relaxation [129]. Incorporating ZnS into MnFe2O4 nanocomposites
highlight the potential of cobalt ferrite in various applications but also (MnFe2O4/ZnS) elevates Ms by 25 % via cation redistribution. Zn2+
emphasize the need for careful consideration of their magnetic proper­ substitution in tetrahedral (A) sites displaces Mn2+, forcing Fe3+
ties when designing devices or treatments utilizing these NPs [126]. migration to octahedral (B) sites. As a result, the MnFe2O4/ZnS nano­
Cobalt ferrite nanoparticles (CFNPs, Co0.65Fe2.35O4) with a 17 nm composite exhibits an enhanced net saturation magnetization compared
average diameter were synthesized via thermal decomposition, followed to MnFe2O4 NPs alone [129].
by hydrophilic coating to enhance water solubility and biocompatibility. Nickel ferrite nanoparticles (NiFe2O4 NPs), despite intrinsic non-
These CFNPs demonstrated superior HT performance compared to cubic biocompatibility, exhibit biomedical utility owing to their high mag­
IONPs, achieving a SAR of 400 Wg-1 under low-frequency AMF (H0 = 20 netic moments (~90 emu⋅g− 1) when functionalized with biocompatible
kAm− 1, f = 105 kHz)—double the SAR of cubic IONPs (200 Wg-1) coatings such as oleic acid and tetramethyl ammonium hydroxide
(Fig. 8) [96]. In murine models, intratumorally CFNP administration (TMAH) [130]. For instance, Umut et al. synthesized superparamagnetic
and three consecutive 30-min AMF cycles (4 kAm− 1, 280 kHz) induced a NiFe2O4 NPs (4.4 nm core, 15 nm hydrodynamic diameter) via
6 ◦ C temperature differential between tumor and distal tail tissue on day co-precipitation, achieving SAR of 4–11 Wg-1 under AMF (H0 =
one, stabilizing at 3.5 ◦ C on days two and three. Despite this attenuation, 17.2–23.7 kAm− 1, f = 170 kHz). Residual hysteresis in magnetization
sustained intratumorally heating confirmed CFNP efficacy. curves arose from interparticle exchange/dipolar interactions within
Manganese ferrite nanoparticles (MnFe2O4 NPs) exhibit negligible aggregates [131]. Comparative studies of 20 nm ferrites reveal CoFe2O4
coercivity, high magnetic susceptibility, and minimal retentivity (<5 NPs yield the highest specific loss power (SLP = 315 Wg-1), out­
emu⋅g − 1), distinguishing them from conventional superparamagnetic performing NiFe2O4 and MnFe2O4 (SLP = 295Wg-1). Notably, increasing
materials. Their biocompatibility, chemical stability, and high Néel CoFe2O4 concentration enhances SLP by 20–30 %, whereas NiFe2O4 and
transition temperatures (>573 K) position them as promising candidates MnFe2O4 exhibit 15–25 % SLP reduction at >0.4 g mL− 1 due to
for MHT and MRI contrast enhancement [127]. Synthesized via the aggregation-induced dipolar coupling losses [132]. These findings

Fig. 8. Characterization of cobalt ferrite nanocubes. (A) Schematic representation of aqueous solution of polymer-coated Co–Fe NCs compatible for biological
application. (B–C) TEM images of PMAO-coated Co–Fe NCs with mean sizes of 17 ± 2 nm. (D) Higher SAR value for Co–Fe NCs at lower clinically relevant AMF
compared to IONCs. (E) No toxicity for IONCs and significant intrinsic toxicity of Co–Fe NCs on cancer cells. Reproduced with permission [96]. Copyright
2020, Wiley.

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underscore ferrite-based MIH as a versatile platform for antitumor composition, hydrophobicity, molecular weight, and stiffness [139,
strategies, validated across preclinical in vitro and in vivo models. 140]. This degree of control often surpasses that attainable with
lipid-based nanomaterials. Specifically, in microbubble technology,
6.2. Organic nanomaterials polymer-shelled microbubbles exhibit several advantages over
lipid-based analogs. These liposomes can bear a greater drug payload
Owing to their superior biodegradability, exceptional biocompati­ owing to their denser shells [141,142] and can be designed to assume
bility, and facile fabrication processes, organic nanomaterials have anisotropic forms, which boosts the efficiency of drug delivery by
garnered significant attention in biomedical research over several de­ optimizing margination characteristics [143,144].
cades. In the specialized field of MHT, organic micro-/nanosystems Nanosystems synthesized via material engineering and synthetic
primarily comprise lipid-based and polymer-based. chemistry strategies often require surface modifications to achieve
physiological stability, biocompatibility, and prolonged circulation for
6.2.1. Lipid-based nanomaterials disease diagnosis and treatment, particularly inorganic platforms. Sur­
Since the groundbreaking discovery of liposomes by Bangham in face functionalization enhances targeted accumulation at lesion sites,
1965, these lipid-based carriers have revolutionized the field of drug enabling precise imaging or therapy with reduced dosages. This prin­
delivery. Liposomes, composed primarily of lipids and fatty acids, have ciple applies universally, including ultrasound-based nanosystems,
shown remarkable biocompatibility and biodegradability, making them where surface engineering—such as PEGylation of MNPs—is critical for
ideal candidates for encapsulating and administering therapeutic mol­ in vivo efficacy. Polymer-coated MNPs exemplify this strategy,
ecules to combat various diseases. Their unique structure consists of combining magnetic separation with ligand-mediated targeting for ap­
amphipathic molecules that self-assemble into a bilayer sphere, with plications like circulating tumor cells (CTCs) isolation [145].
hydrophilic head groups facing the exterior aqueous environment and CTCs, shed from primary tumors into peripheral blood, are rare
hydrocarbon chains residing within the hydrophobic interior [133]. The targets crucial for cancer diagnostics. Immunomagnetic separation le­
versatility of liposomes as drug carriers lies in their amphiphilic nature, verages polymer-coated MNPs for CTCs enrichment, offering high cap­
which allows them to encapsulate molecules of varying polarities ture efficiency and specificity through ligands (e.g., antibodies [146],
effectively [134]. By encapsulating drugs within liposomes, systemic aptamers [147]) targeting CTCs-specific biomarkers. The polymer
toxicity can be minimized, and dosing regimens can be more easily coating stabilizes the magnetic core, provides biocompatibility, and fa­
tolerated, particularly in treatments for cancer [135]. The combination cilitates functionalization. Upon exposure to blood, ligand-receptor in­
of thermosensitive liposomes with HT could revolutionize the treatment teractions selectively bind CTCs, while an external AMF isolates
of cancer by improving drug delivery and minimizing off-target effects. CTCs-MNP complexes from blood components, minimizing contamina­
Ongoing research in this field continues to explore novel strategies to tion and enhancing downstream analytical sensitivity.
enhance the efficacy and performance of temperature-sensitive lipo­ Synthetic polymers (e.g., PEG, PDA, polyvinylpyrrolidone) and nat­
somes (TSLs) for targeted drug delivery applications. The use of pure ural polymers (e.g., chitosan, alginate, and dextran) are widely used as
1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes is often coatings, balancing stability, biocompatibility, and functional group
limited by incomplete drug release, prompting researchers to incorpo­ availability. For instance, Wang et al. designed hydrogel-coated MNPs
rate additional phospholipids like DSPC and HSPC to improve drug functionalized with anti-EpCAM antibodies via methacrylic acid link­
release rates. In a seminal study by Yatvin et al., in 1978 [136], a ages [148], enabling CTCs capture with minimal nonspecific adhesion.
mixture of DPPC and DSPC in a 3:1 M ratio was shown to enhance drug GSH-mediated disulfide bond cleavage facilitated MNPs release while
release significantly when exposed to serum, especially at elevated maintaining >95 % CTC viability post-separation. Optimization of
temperatures. The encapsulation efficiency of DSPC was nearly perfect polymer coating remains pivotal for advancing CTC-based clinical di­
in experiments involving localized mild HT in human BLM melanoma agnostics [149].
NMRI nude mice, highlighting its potential in optimizing drug release In addition to CTC isolation, polymer-based hydrogel materials also
kinetics. Further advancements in liposomal formulations were made by exhibit unique advantages in the field of cancer therapy. For example,
Needham et al. [137], who introduced lysolipids such as MPPC and magnetic colloidal hydrogels can achieve precise delivery of liver cancer
MSPC in conjunction with lipid-grafted polyethylene glycol (PEG) and ablators through minimally invasive percutaneous injection [150], and
DPPC to create a novel temperature-sensitive liposomal doxorubicin their injectable properties can adapt to irregular tumor shapes to
(DOX) formulation known as ThermoDox®. This formulation is improve treatment coverage [151]. The hydrogel matrix can not only
currently undergoing phase III clinical trials and shows promise in adsorb chemotherapeutic drugs or thermal ablators but also be guided to
improving drug release at specific temperatures. In a separate study, the tumor site by an external magnetic field, avoiding the trauma of
Tatsuaki et al. developed a TSLs formulation composed of DPPC and traditional surgery. In the postoperative treatment of hepatocellular
Brij78 in a molar ratio of 96:4 and compared it to TSLs containing carcinoma, injectable magnetic montmorillonite colloidal hydrogels are
lysolipids [138]. The results indicated that the novel TSLs formulation enriched in residual lesions through magnetic targeting [152] (Fig. 9),
displayed an increased drug release rate at elevated temperatures, while utilizing the layered structure of montmorillonite for sustained drug
maintaining stability at lower temperatures. The incorporation of pal­ release while enhancing local magnetic responsiveness to reduce the risk
mitoyl lysophosphatidylcholine (P-lyso-PC) in liposomes was also noted of postoperative recurrence. The three-dimensional network structure of
to enhance stability and operational efficiency, ultimately improving the hydrogels enables synergistic delivery of drugs and hyperthermia,
performance of liposomal drug delivery systems. Overall, the integration providing an integrated platform for multidisciplinary cancer treatment
of additional phospholipids and innovative formulations has paved the [153,154]. These studies demonstrate that hydrogels, as an important
way for more efficient drug release mechanisms in liposomal systems. branch of polymer-based materials, significantly enhance the precision
The use of synthetic phospholipids like P-lyso-PC holds great promise in and safety of cancer therapy by integrating multiple properties such as
enhancing the stability and functionality of liposomes, offering a po­ magnetic targeting, thermal responsiveness, and biodegradability,
tential solution to the challenges posed by incomplete drug release in showcasing broad prospects for translation from laboratory to clinic.
traditional liposomal formulations.
7. Combination of MHT with other treatments
6.2.2. Polymer-based nanomaterials
Polymerbased nanomaterials are renowned for their versatility, The destruction of tumors via single modality MHT necessitates high
providing extensive control over their physicochemical properties temperatures, thereby elevating the risk of damage to neighboring tis­
through the customization of polymer chain attributes like monomer sue. Furthermore, the efficacy of single MHT on the entire tumor mass is

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 9. Preparation and Characterization of Magnetic Composite Hydrogel (MCH). (A) Gelation process and inverted fluorescence microscope images. Green: Fe3O4
NPs, red: gelatin NPs. (B) Zeta potential values at different pH values. (C) Trend of mixed particle size. (D) Storage modules and loss modules. (E) Shear rate scanning
viscosity and injection image illustrations. (F) i) SEM images of Fe3O4 NPs and ii) SEM images of gelatin NPs. (G) Scanning electron microscope image of MCH and
corresponding elemental mapping analysis. Reproduced with permission [152]. Copyright 2024, Wiley.

often inadequate due to the uneven distribution of heat. To address these achieve efficient PTT conversion. Moreover, gold-silica nanostructures
challenges, research has focused on magnetic hyperthermia-based have demonstrated biosafety in early prostate cancer trials, yet NIR’s
combination therapy (MHCT). Integrating MHT with radiotherapy, limited penetration depth (5–10 mm) restricts PTT to superficial tumors.
chemotherapy, immunotherapy, and other treatments is viewed as a The integration of MHT and PTT enables thermal ablation of
promising strategy for synergistic intervention (Fig. 10) [155–158]. deep-seated tumors by leveraging AMF to activate MNPs, thereby cir­
MHCT not only enables the complete eradication of tumors with reduced cumventing tissue penetration limitations. This synergistic effect origi­
AMF intensity and lower drug dosages but also minimizes harm to the nates from the dual-modality energy-responsive characteristics of MNPs,
surrounding healthy tissue, resulting in highly effective treatment with which facilitate efficient energy accumulation through coupled mag­
diminished side effects [88,159–162]. Moreover, the combination of netic moment relaxation and photoabsorption. Such dual-modality
MHT with other thermal therapies can compensate for the limitations of design allows NPs to concurrently harness magnetic energy (deep-­
individual thermal treatments and optimize their therapeutic benefits. tissue penetration) and photonic energy (spatially precise targeting),
We also analyze the clinical use and prospects of several combination establishing a spatiotemporally coordinated heating network.
therapies. MNPs have been confirmed to be efficient magnetic-photothermal
combined agents in the NIR window [166–171]. According to existing
research results, this concept of antitumor nanotherapy based on iron
7.1. MHT and photothermal-combinational therapy oxide cores can locally increase the temperature in vitro through only
magnetic and light-induced hyperthermia, leading to the complete
For standalone MHT, the currently available MNPs exhibit low destruction of cancer cells and achieving complete tumor ablation in
power absorption efficiency, necessitating either impractically high- vivo [170]. Although the iron oxide component of MNPs can already
intensity AMF or elevated NPs doses. While PTT, which generates heat ensure potential photothermal conversion functions, magnetic hybrid
via non-radiative electron relaxation in light-absorbing materials (e.g., nanoplatforms should continue to be used for cancer theranostics. By
cyanine, phthalocyanine) [163]. Early PTT agents were plasmonic ma­ decorating iron oxide cores with gold and silver nanoparticles as typical
terials such as gold (Au), silver (Ag), and copper chalcogenides (Cu2-xE, modifiers, the performance of iron oxide cores can be significantly
E = S, Se, Te, O) [164,165], because these materials have the minimum enhanced, thereby generating hybrid nanosystems with synergistic
tissue scattering characteristics in the NIR (650–950 nm) and can

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 10. Schematic diagram of combining anti-tumor therapy with MHT and other treatments.

magnetic and light-excited properties. For combined MHT-PTT pro­ deep-seated tumors remains a significant challenge. MHT offers distinct
tocols, they generally involve intratumoral administration of MNPs advantages for solving the question due to its unrestricted tissue pene­
followed by synchronized application of AMF and NIR laser exposure to tration. The deep-seated mechanisms of this synergistic effect stem from
achieve dual-modal thermal ablation. Espinosa et al. engineered iron the multi-faceted regulation of tumor biological characteristics by MHT:
oxide-gold hybrid nanoassemblies that enhance heating via dual
magnetic-plasmonic properties, achieving SAR up to 5000 Wg-1 in 1. Microenvironmental reoxygenation: local HT dilates normal blood
dual-mode (AMF: H0 = 20 kAm− 1, f = 110 kHz; NIR: 808 nm laser) vessels to promote oxygen delivery. Meanwhile, the disordered
[172]. This approach amplifies heating efficiency 2–5 times compared tumor blood vessels produce a thermal sealing effect, selectively
with MHT alone, inducing apoptosis-mediated tumor regression in vivo. increasing the intertumoral temperature (ΔT>5 ◦ C) and reversing
Despite the synergistic potential of combined photothermal and hypoxia-induced radiotherapy resistance [175].
magnetic heating therapies to address individual modality limitations, 2. Inhibition of DNA repair: Hyperthermia (>41 ◦ C) disrupts the ho­
clinical adoption remains limited. Key barriers include: multiparametric mologous recombination repair (HRR) pathway by ubiquitinating
optimization complexity, therapeutic consistency, metabolic variability, and degrading BRCA2/FANCD2 proteins, reducing the repair effi­
safety-efficacy trade-offs, cost constraint and specialized operator de­ ciency of radiation - induced DNA double - strand breaks [175].
mands. Nonetheless, the integration of magnetic and photothermal 3. Metabolic sensitization: heat shock increases the permeability of
modalities demonstrates transformative potential for tumor ablation, as tumor cell membranes, promoting the influx of radiotherapy sensi­
evidenced by preclinical efficacy. tizers (such as oxygen free radicals). At the same time, the acidic
microenvironment enhances the cytotoxicity of thermal damage
[181].
7.2. MHT in combination with radiotherapy
This spatiotemporal synergy allows the radiation dose to be reduced
Hypoxic TMEs arise from aberrant vasculature, which differs mark­ without affecting the curative effect, making it particularly suitable for
edly from normal vascular networks [173]. This oxygen-deprived state the precise targeted treatment of deep-seated tumors (such as gliomas
contributes to tumor cell radioresistance [174], a challenge addressed and prostate cancer).
by combining radiotherapy with HT to exploit the heightened thermal Combination therapy necessitates precise control to optimize thera­
sensitivity of hypoxic cells [175]. While normal tissues exhibit vasodi­ peutic outcomes. The sequence and timing of HT and radiotherapy
lation and increased perfusion under hyperthermia, the disorganized critically influence their synergistic capacity to damage cancer cells.
vasculature of tumors impedes heat dissipation, resulting in localized Edward et al. demonstrated that minimizing the interval between irra­
thermal entrapment. Furthermore, lactic acid accumulation in hypoxic diation and HT maximizes tumor cell death in murine models, while
regions acidifies the TME, potentiating heat-induced cytotoxicity [176]. delays exceeding 4 h reduced radiosensitization efficacy [182]. Notably,
Preclinical and clinical studies have explored integrating radiotherapy moderate HT (39–42 ◦ C) can induce transient resistance to subsequent
with external heat modalities [177–180]. However, effective heating of

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heat exposure, termed thermotolerance, necessitating strategic sched­ 7.3. MHT in combination with chemotherapy
uling of therapies [183]. Current protocols prioritize irradiating tumors
before administering MNPs and initiating MHT to mitigate this adaptive In the domains of materials chemistry and pharmacology, consider­
response. A pivotal phase II clinical trial by Hauff et al. (2011) evaluated able research is focused on the development of advanced MNP-based
combined MHT and radiotherapy in 66 recurrent GBM patients [28]. platforms. These efforts seek to leverage the dual benefits of MNPs as
Intratumoral IONPs were activated via AMF alongside fractionated effective thermal agents and as carriers for chemotherapeutic drugs.
stereotactic radiotherapy, demonstrating improved survival and toler­ Additionally, there is an emphasis on designing intelligent magnetic
ability compared to standard care. This study established foundational nanoplatforms capable of loading and releasing chemotherapeutic
clinical evidence for dual-modality therapy. Advances in magnetic agents in a more controlled and targeted manner [185–187]. On one
nanomaterials, such as gadolinium-doped iron oxide nanoparticles hand, the heat produced during the MHT process serves as an external
(Gd-IONPs), further enable real-time tracking of therapeutic responses stimulus, initiating drug release through a thermally driven mechanism.
via MRI. Jiang et al. reported Gd-IONPs with enhanced SAR over con­ On the other hand, the unique tumor conditions provide a special
ventional Fe3O4 [184], facilitating simultaneous particle tracing and HT microenvironment in which different intratumoral stimuli (e.g., acidic
in TRAMP-C1 prostate adenocarcinoma models. Gd-IONP-mediated HT pH or hypoxic and pro-oxidative states) can promote controlled drug
combined with radiotherapy extended tumor growth delay (10 days vs release. The synergistic enhancement between MHT and chemotherapy
4.5 days for radiotherapy alone) and reduced hypoxia via vascular is primarily based on the following aspects: 1. Heat-enhanced drug
disruption and necrosis. Mechanistically, HT enhances radiotherapy penetration: local HT dilates tumor blood vessels and increases vascular
efficacy through thermal ablation (>45 ◦ C) and hypothermic (39–42 ◦ C) permeability, promoting the extravasation of nanocarriers while
reoxygenation. Collectively, MHT-Radiotherapy synergy offers three reducing interstitial fluid pressure (IFP) to accelerate drug diffusion
key advantages: enhanced tumor cytotoxicity, reduced radiotherapy [188]. 2.Thermochemosensitization: many drugs exhibit chemothera­
doses and associated normal tissue toxicity, and improved targeting of peutic sensitization to tumor cells at temperatures between 40 and
deep-seated tumors. 42 ◦ C. Experimental animal studies show that combining HT with
TSL-mediated drug delivery significantly increases drug concentrations
in tumors compared to free drugs [189]. 3. Spatiotemporal precise

Fig. 11. Characterization of the MIDENs. (A) TEM images of SPIONs and MIDENs. (B) Differential scanning calorimetry of PLGA polymers of different compositions.
(C) Dynamic light scattering of SPIONs, PLGA/SPIONs, and MIDENs. (D) FTIR spectra of PLGA, MIDENs, and SPIONs. (E)Vibrating sample magnetometer plots of
SPIONs and MIDENs. (F) T2-weighted MR images of MIDENs with various Fe concentrations. (G) T2 relaxation rate (1/T2) of MIDENs with various Fe concentrations.
Reproduced with permission [191]. Copyright 2018, Elsevier.

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

controlled release: PH/heat dual-responsive materials (such as magnetic curcumin nanoparticles (termed mCNPs) and per­
poly-NIPAM copolymers) achieve pulsed drug release triggered by AMF, fluoropentane (PFP) to enhance their water solubility [198]. The plat­
leading to significantly higher local tumor drug concentrations than form integrated magnetizable polymethyl methacrylate (PMMA) bone
intravenous injection while reducing systemic toxicity. cement, containing Fe3O4 and Nd2Fe14B magnetic particles, to reinforce
Based on the above facts, many studies have used stimulatory the mechanical properties of bone tissue. This system leverages
chemical materials with thermo-responsive and/or pH-responsive AMF-induced magnetothermal effects to drive the release of chemo­
properties to achieve on-demand selective release of drugs during therapeutic drugs, providing targeted magneto-thermo-chemotherapy
MHT [190]. Thirunavukkarasu et al. constructed smart NPs consisting of and multimodal treatment for bone mechanical enhancement. Prom­
poly(lactic acid)-vinyl acrylate (PLGA), SPION, and DOX to realize ising tumor suppression effects were observed in the 143b osteosarcoma
efficient MRI-induced dual cancer therapy with AMF-induced dual model (Fig. 12), although further research is required to ensure
therapy NPs: magnetic fluid inducible drug-eluting nanoparticles long-term stability and safety.
(MIDENs) [191]. The particles can respond to external AMF-generated
heat while simultaneously releasing drugs embedded in the NPs 7.4. MHT in combination with immunotherapy
(Fig. 11). In vitro studies have shown that MIDENs are cytocompatible
and allow for magnetic imaging, heat generation, and active release of The fundamental goal of cancer immunotherapy is to disrupt tumor
DOX in AMF applications. Furthermore, in vivo experiments have immune escape mechanisms and enhance the immune system’s capacity
demonstrated that MIDENs facilitate in vivo MRI imaging and that to recognize and eliminate malignancies [199,200]. This concept traces
thermochemotherapy induced by AMF is superior to other materials or back to Dr. Coley’s 1890s discovery, which first established a direct link
methods examined in suppressing the growth of highly aggressive between elevated body temperature (e.g., fever) and amplified immune
tumors. responses against tumors. Both exogenous hyperthermia and endoge­
Moreover, the most cutting-edge preclinical validation of pH- nous fever stimulate intratumoral immune cells through the following
responsive nanosystems has been demonstrated in the field of MRI- mechanisms.
based signal detection. T1 (Gd-based) or T2 (IONPs) contrasts are used
to track the delivery of pH nanosystems, and this application can be 1. Local HT induces immunogenic cell death in tumor cells, triggering
further used to detect different types of solid tumors. Polymers that the following cascade reactions: (1) Release of damage-associated
respond to changes in pH are sensitive to the acidic environment at the molecular patterns (DAMPs), including signaling molecules such as
site of pathology, leading to alterations in T2 contrast. A similar system high-mobility group protein B1 (HMGB1), ATP, and calreticulin
could be used to identify other regions with acidic conditions, such as (CRT). (2) Upon recognition of DAMPs by tumor-associated dendritic
tumors, or to improve the planning of combination therapies. Specif­ cells (TADCs), DCs are driven to mature into antigen-presenting cells
ically, pH-sensitive nanosystems that modulate both pH and T2 contrast (APCs). Among them, HSPs, as a subset of DAMPs, can directly
can provide valuable insights into drug release from carriers and enable promote the migration of DCs to lymph nodes and activate natural
more precise predictions regarding the optimal timing for MHT to killer T cells (NKT cells) and T lymphocytes (T cells) [194,201]. (3)
maximize synergistic effects. Sasikala et al. engineered mussel-inspired Additionally, calreticulin, a potent immunostimulatory protein in
poly(HEMA-co-DMA)-functionalized SPIONs for pH-responsive de­ DAMPs, is crucial for Ca2+ homeostasis and glycoprotein folding, and
livery of bortezomib (BTZ) and MHT [192]. The copolymer’s multi­ is believed to play a role in immunogenic cell death and other
dentate catechol motifs enhanced colloidal stability and ligand extracellular functions [202]. When calreticulin binds to lipoprotein
anchoring, enabling dual thermo-chemotherapeutic action: localized receptors on TADCs, it activates a key phagocytic signal to promote
BTZ release under acidic conditions and heat generation via the maturation of TADCs into APCs [203].
Néel/Brownian relaxation. In vitro/in vivo studies validated synergistic 2. Reprogramming of the immune checkpoint microenvironment: HT
tumor suppression, positioning these nanoplatforms as precision reverses the immunosuppressive state of tumors by regulating
oncology tools. signaling axes [204]. The response rate of immune checkpoint in­
Existing MHT platforms can be broadly categorized into two types: hibitors (ICIs) has been confirmed to be positively correlated with
MNP-based systems and liquid/solid metal implant-based platforms tumor mutational burden (TMB). Ultra-hyperthermia (>50 ◦ C) can
[159,193,194]. For the former, shape- and size-tunable MNPs (e.g., enhance TMB by damaging DNA and promoting the release of tumor
FeNPs, Fe2O3NPs, and Fe3O4 NPs) were synthesized, and their high neoantigens, thereby largely inducing specific and nonspecific im­
specific surface area enabled them to load drugs efficiently. Neverthe­ munity [205]. Rangamuwa et al. observed that 80 % of patients
less, MNPs that rely on relaxation and hysteresis loss mechanisms to receiving bronchoscopic hot steam ablation showed upregulation of
produce magnetothermal effects generally fall short in achieving high PD-L1 expression [206], suggesting and possibly validating that HT
MHT performance. This is the case even when they are synthesized can convert "cold tumors" into "hot tumors". Additionally, the
through elaborate, complex procedures, under rigorous reaction condi­ numbers of Tregs [207] and Th17 cells [208] have been shown to
tions, and undergo subsequent modifications [195,196]. As a result, decrease significantly after HT, which alleviates immunosuppression
magnetothermal therapy based on MNPs requires repetitive drug de­ to a certain extent.
livery and high-power AMF, which severely hampers its biological ap­ 3. HT mediates bidirectional regulation of cytokines to achieve directed
plications. Conversely, large-scale (millimeter-sized) metallic implants activation of the cytokine network: (1) Surge in pro-inflammatory
featuring continuous metallic structures demonstrate potent magneto­ cytokines: Upregulates the secretion of pro-immune factors such as
thermal capabilities, capable of producing intense heat via eddy current IL-12 and IL-23α, activating cytotoxic T lymphocytes (CTLs) and
thermal effects even when exposed to low-power AMF [197]. None­ enhancing their tumor-infiltrating capacity; (2) Inhibition of anti-
theless, metallic implants with compact structures and minimal surface inflammatory cytokines: Suppresses immunosuppressive cytokines
area typically necessitate intricate etching or plating procedures to such as VEGF and PDGF-AA, blocking tumor angiogenesis and
attain a modest level of drug loading, a process that significantly com­ recruitment of myeloid-derived suppressor cells (MDSCs) [209].
plicates the drug loading and diminishes its efficiency. Crafting a
magneto-thermal combination therapy platform that boasts exceptional HT systematically activates anti-tumor immune responses through
MHT efficiency along with convenient and effective drug loading ca­ multiple synergistic mechanisms, providing a theoretical basis for the
pabilities, while satisfying clinical requirements, undoubtedly poses a combined application of MHT and immune therapy. This multi-
significant challenge. Recently, Liang et al. developed a multifunctional dimensional immune activation strategy not only improves local
biomimetic bone magnet (BBM) platform triggered by an AMF, utilizing tumor control rates but also opens new pathways for the treatment of

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 12. In vivo therapeutic MHT efficacy of BBMs alliance mCNPs. (A) Treatment and follow-up regimen. (B) 2D (left) and 3D (right) infrared thermal images of
143B tumor-bearing mice injected with PBS and BBMs exposed to AMF at different time intervals and (C) corresponding temperature–time curve for the tumors. (D)
Representative images of 143B tumor-bearing mice 21 days after various treatments. (E) Body weights. (F) Tumor growth curve. Reproduced with permission [198].
Copyright 2023, Elsevier.

metastatic tumors by inducing systemic immune memory. immunotherapy. Nishikawa et al. demonstrated that combining MHT
with glycyrrhizin (an HMGB1 inhibitor), CpG oligodeoxynucleotides,
7.4.1. DAMPs expression and MHT and checkpoint blockers (anti-PD-1/anti-CTLA-4) eradicated poorly
DAMPs, including HMGB1, HSPs, uric acid, hyaluronic acid frag­ immunogenic B16-F10 melanoma in C57BL/6 mice by suppressing
ments, acetylheparin sulfate, and ATP, play dual roles in tumor immu­ HMGB1-mediated inflammation while enhancing systemic antitumor
nology. HMGB1, released during cell death, functions both as a DAMP immunity [212].
and a cytokine, binding to Toll-like receptors (TLR2/4) and the receptor HSPs similarly exhibit context-dependent roles: they confer resis­
for advanced glycation end products (RAGE) to stimulate pro- tance to hyperthermia-induced cytotoxicity and promote angiogenesis/
inflammatory cytokine release (e.g., TNF-α) [210,211]. Paradoxically, metastasis, yet their release during necrosis activates DCs via "danger
while HMGB1 promotes vascular endothelial proliferation and neo­ signal" recognition, triggering antigen-presenting cell maturation and
intima formation—potentially driving tumor progression—its prolonged immune responses. Sato et al. leveraged this duality by
hyperthermia-induced overexpression can synergize with functionalizing silane-coated Fe3O4 nanoparticles with N-propionyl-4-S-

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cysteinylaminophenol to enhance melanoma cell uptake [213]. In cytokines (e.g., IL-1β, IL-2, IL-6, IL-12, IL-23α, CCL2, TNF-α) in murine
B16-OVA xenografts, MHT (118 kHz, 30.6 kAm− 1, 30 min) induced and human macrophages [226], though outcomes depend on SPION
tumor necrosis and HSP expression, activating DCs and achieving surface chemistry and cellular context. For example,
complete regression without recurrence—even after contralateral tumor carboxydextran-coated SPIONs enhance IL-12 in bone marrow-derived
rechallenge. This underscores MHT’s potential to prime adaptive im­ macrophages, whereas dimercaptosuccinic acid (DMSA) or 3-aminopro­
munity against metastatic lesions. pyltriethoxysilane (APS) coatings show no such effect [227,228].
Contrary to the HSPs overexpression strategy, another group Notably, dextran-coated SPIONs induce IL-1β and TNF-α in human pe­
exploited gene therapy to downregulate HSPs. Gupta et al. pioneered an ripheral blood mononuclear cells at levels comparable to lipopolysac­
immunologically synergistic glioma therapy combining HSP90 sup­ charide (LPS) stimulation [229], a finding warranting further
pression with MHCT. Differential HSP expressions in glioma cells under investigation for intravenous applications. SPIONs also variably modu­
varied immunosuppressive TME models (2D/3D monoculture, co- late anti-inflammatory cytokines: IL-10 expression fluctuates inconsis­
culture spheroids) revealed HSP90 upregulation post-MHCT. Co- tently across murine (RAW264.7) and human macrophages depending
administration of the HSP90 inhibitor 17-DMAG enhanced MHCT effi­ on [228,230], while DMSA/APS-coated SPIONs elevate TGF-β in
cacy, reducing primary/secondary tumors by 65 % and 53 % within 8 THP-1-derived macrophages. Additionally, SPIONs suppress VEGF—a
days, achieving complete suppression by day 20. Extracellular HSP90 pro-angiogenic marker—in RAW264.7 cells, suggesting potential
from necrotic cells triggered IFN-γ and calreticulin upregulation, indi­ anti-angiogenic effects meriting exploration in human models.
cating systemic immunological reaction. This synergy arises from
multimodal mechanisms: AMF-driven HT, HSP90 inhibition, and 7.4.3. Immune checkpoint Blockade(ICB) and MHT
DAMPs-mediated DC/cytotoxic T-lymphocyte (CTL) activation. Under normal physiological conditions, the human immune system
To further enhance the therapeutic effect, researchers have devel­ identifies and eliminates foreign pathogens and aberrant cells. To pre­
oped a hybrid nanosystem [214], which combines the advantages of vent excessive activation, regulatory mechanisms such as immune
magnetic-thermal therapy and immunomodulation. Called SPIOs + checkpoints (e.g., CTLA-4 and PD-1/PD-L1) modulate immune re­
Magnetic-thermal sensitive phase-transition nanodroplets (RPPs), this sponses. CTLA-4 operates during early immune activation by binding to
nanosystem utilizes phase-transition nanodroplets with immunomodu­ APC surface molecules, thereby restricting T-cell proliferation. In
lation to enhance the efficacy of mild magnetic-thermal therapy (below contrast, PD-1 interacts with PD-L1—expressed on both normal and
44 ◦ C). The nanodroplets consist of the immunoadjuvant Resiquimod tumor cells—during the effector phase to suppress T-cell activity. ICIs
(R848) and the phase-change agent perfluoropentane (PFP) encapsu­ are therapeutic agents designed to block these regulatory molecules.
lated in a PLGA shell to form the RPPs. In the presence of the RPPs, the Among these, CTLA-4 and PD-1/PD-L1 inhibitors represent foundational
microbubble-induced cavitation phenomenon reduces the temperature ICI classes [231]. The FDA’s 2011 approval of ipilimumab, a
threshold required for MHT from 50 ◦ C to approximately 44 ◦ C. CTLA-4-blocking antibody, marked the clinical introduction of ICIs.
Cavitation-induced cell membrane disruption resulted in increased These therapies are now integral to managing malignancies such as
release and exposure of DAMPs, including passively released HMGB1, melanoma, non-small-cell lung cancer (NSCLC), gastrointestinal can­
actively secreted ATP, and surface-exposed CRT (Fig. 13) [215]. This cers, renal cell carcinoma, breast cancer, and hematologic cancers. In
process effectively converts “cold” tumors that are less responsive to melanoma, PD-1 inhibitors nivolumab and pembrolizumab have
immunotherapy into “hot” tumors, reversing the TME and making tu­ significantly improved survival outcomes, securing their status as
mors more amenable to immunotherapy. R848 is a potent activator of first-line treatments. For NSCLC, combined regimens involving
TLR-7/8, which acts as immune adjuvants in this nanosystem [216,217]. PD-1/PD-L1 inhibitors and chemotherapy yield remission rates of
When bound to MHT-released DAMPs, R848 is recognized by Toll-like 37.3–45.3 % and a median overall survival of 15.6 months. Neoadjuvant
receptors (TLRs), which activate DCs. This activation is characterized immunotherapy demonstrates a 38 % major pathological response rate
by up regulation of the co-stimulatory factors CD80 and CD86, which in early-stage NSCLC. In metastatic colorectal cancer, PD-1 mono­
are hallmarks of mature DCs. The shift in DC phenotype from immu­ therapy shows efficacy, particularly in patients with defective mismatch
nosuppressive to immunogenic further enhances the immune response repair or high microsatellite instability. Dual PD-1/CTLA-4 inhibition
against tumor cells [218,219]. The mature DCs then acquire an outperforms monotherapy in some contexts, emerging as a preferred
enhanced ability for antigen cross-presentation and secrete various first-line option [232,233]. However, ICIs face limitations. First, mon­
pro-inflammatory cytokines [220–222], including interleukin-6 (IL-6), otherapy efficacy is often constrained by intrinsic or acquired resistance,
interleukin-12 (IL-12), and tumor necrosis factor (TNF-), which modu­ mediated by antigen loss, compensatory immunosuppressive pathways,
late the anti-tumor immune response. This cascade ultimately promotes or infiltration of regulatory immune cells. Second, immune-related
the activation of CTLs to eliminate tumors [223]. Quantitative assay adverse events—including pneumonitis, hepatitis, endocrine dysfunc­
results can be seen in a 72.39 % increase in the exposure of CRT on the tion (e.g., thyroid abnormalities), dermatitis, and colitis—arise from
cell membrane and a 45.84 % increase in the release of HMGB1 in vivo. systemic immune activation against healthy tissues [232,234–237].
In addition, the maturation rate of DCs increased from 4.17 % to 61.33 The integration of MHT with ICB represents a transformative strat­
% and the infiltration rate of CTLs increased from 10.44 % to 35.68 %. egy in oncology, leveraging nanoparticle-mediated thermal ablation to
The hybrid nanosystem treatment effectively inhibited contralateral and prime systemic antitumor immunity. Chao et al. demonstrated this
lung metastases, a result attributed to the combined impact of mild MHT synergy using PEG/dopamine-coated IONPs (30–50 nm) co-
and immunostimulatory effects. encapsulated with imiquimod (TLR7 agonist) in PLGA nanocapsules
[238]. Intertumoral injection followed by AMF exposure (Hf = 1.2 × 109
7.4.2. Cytokines and MHT Am− 1s− 1, 50–52 ◦ C) induced primary tumor regression and elicited an
Cytokines, a class of signaling proteins, critically regulate immune abscopal effect—suppressing contralateral metastases via cytotoxic
and inflammatory responses by potentiating cytotoxic T lymphocyte T-cell activation. Systemic anti-CTLA-4 administration amplified this
activity. Clinically explored cytokines include interferon (IFN) variants response, achieving complete tumor eradication. Wang et al. advanced
(α, β, γ), tumor necrosis factor (TNF), colony-stimulating factors (CSFs), this paradigm by engineering Janus-type nanospheres (250 × 100 nm)
and interleukins (IL-2, IL-6, IL-12) [224]. Despite preclinical promise, comprising Fe3O4 heads and disulfide-bridged mesoporous silica tails
cytokine monotherapies underperform in clinical trials due to short loaded with chlorin e6 (Ce6) [239]. In orthotopic 4T1 breast cancer
half-lives and narrow therapeutic windows [225]. Emerging strategies models, sequential MHT (25.8 kAm− 1, 262 kHz, 20 min) and photody­
propose synergizing cytokines with MHT, leveraging SPIONs to amplify namic therapy (PDT) (660 nm laser, 0.15 W cm− 2, 10 min) triggered
immunomodulation. SPION-based MHT upregulates pro-inflammatory immunogenic cell death, DC maturation, and CTLA-4

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 13. The enhanced ICD in vitro mediated by RPPs potentiated mild MHT. (A) LSCM images of calcein-AM/PI-stained 4T1 cells under different treatment
conditions. (B) Quantitative analysis of (A). (C, D) Flow cytometry analysis of cell apoptosis after different therapies. (E) Western blot analysis of HMGB1 and ATP
expression in cells after various treatments. (F, G) Quantitative levels of HMGB1 and ATP in 4T1 tumors after various treatments determined by Western blot analysis.
(H, I) ELISA kit analysis of the released HMGB1 and ATP in the cell supernatant. Reproduced with permission [214]. Copyright 2023, Springer Nature.

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

blockade-enhanced T-cell cytotoxicity. This tri-modal therapy (MHT + which normally block anti-tumor T-cell activity. In addition, the com­
PDT + ICB) eradicated primary tumors and prevented metastasis with bination therapy prevented distant tumor progression in an extraper­
superior efficacy to monotherapies, underscoring the potential of itoneal tumor model. These findings underscore the synergistic potential
thermal-immunological synergy in overcoming tumor resistance. Liu of MHT in combination with ICB in enhancing anti-tumor immune re­
et al. treated orthotopic 4T1 breast tumors with MHT every other day sponses and preventing metastasis. And in a study by Gao et al. the re­
using PEGylated vortexed watershed IONPs (150.9 nm) and intraperi­ searchers developed temperature-responsive iron oxide nano-assemblies
toneal injections of anti-PD-L1 antibodies [240]. MHT was performed (IONA) using cross-linked IONPs loaded with JQ1 (JQ1/IONA) [241],
using alternating current at f = 365 kHz, but H values were not reported an immunomodulator known to down-regulate PD-L1. IONA + AMF
(Fig. 14). Treatments were administered in multiple cycles every two heated to ~45 ◦ C exhibited better immune response and antitumor ef­
days. The study observed that mild HT eradicated primary tumors fects compared to IONPs + AMF (~41 ◦ C) and unresponsive
treated with thermal injury. More importantly, it prompted an 88 % nano-assemblies (uIONA) + AMF (~50 ◦ C).The combination of
increase in cytotoxic CD8+ T lymphocyte infiltration in distant tumors, JQ1/IONPs + AMF further combined mild thermal therapy with
which sensitized them to PD-L1 checkpoint blockers and triggered controlled release of JQ1, resulting in complete elimination of primary
immunotherapy (Fig. 15). The team also found that combination ther­ tumors and induced a potent immune effect of tumor suppression. This
apy attenuated the tumor’s immunosuppressive mechanisms, as evi­ triggered a potent immune effect of inhibiting distant tumor growth and
denced by a marked reduction in myeloid-derived suppressor cells, preventing tumor recurrence and metastasis (Fig. 16). The synergistic

Fig. 14. Characterization of PEGylated FVIOs. (A) TEM and (B) HRTEM images of PEGylated FVIOs. (C) Lorentz TEM image of PEGylated FVIOs. (D) Hydrodynamic
diameter of PEGylated FVIOs. (E) Hydrodynamic size measured as a function of time upon incubation in de-ionized (DI) water, pH 7.4 PBS, and DMEM. Reproduced
with permission [240]. Copyright 2019, American Chemical Society.

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 15. Graph showing the proportion of T-cell-related factors. (A) Representative multispectral fluorescence images of distant tumors after staining immunoflu­
orescence. (B) The percentages of related tumors infiltrating T cells in the distant tumors. Reproduced with permission [240]. Copyright 2019, American Chemi­
cal Society.

effects observed in these studies can be attributed to multiple mecha­ advanced therapies may pose a barrier to their widespread use. More
nisms. First, HT induced by MHT and/or PDT triggers immune cell and more trials continue to confirm the remarkable effectiveness of the
death, leading to the release of tumor-associated antigens. These anti­ combination of MHT and ICIs in activating the immune system, not only
gens activate DCs, which then migrate to lymph nodes and prime to achieve better anti-tumor efficacy, but also to reduce the body’s
anti-tumor T cells. Second, ICIs can block inhibitory signals used by resistance and adverse reactions to the use of a single ICI.
tumors to evade immune surveillance, thereby enhancing the cytotoxic Overall, the combined antitumor regimen of magnetothermal ther­
activity of T cells. Third, the combination of thermotherapy and ICB apy and immunization is still far from clinical popularity. Currently, two
produces a “vaccination”-like effect, where the eradication of the pri­ clinical trials (NCT03757858 and NCT03393858) are in the phase I/II
mary tumor generates a powerful immune memory response. This validation stage, exploring the combination of immunotherapy with
response allows the immune system to recognize and eliminate distant thermotherapy; however, neither of these studies includes MHT [242].
tumor cells, thereby preventing recurrence and metastasis. Over the past two decades, the integration of MHT with immunotherapy
Despite the encouraging results of these studies, clinical translation has gained traction as a promising strategy, known as
of these combined strategies still faces several challenges. First, the thermos-immunotherapy, which offers a more targeted treatment. This
biodistribution and clearance of MNPs need to be carefully controlled to approach is capable of elevating temperatures specifically at the tumor
ensure their safety and efficacy. Second, the optimal dosage and timing site, thereby enhancing heat dissipation and stimulating the local im­
of ICIs need to be determined to maximize their synergistic effects with mune response more effectively [243]. The initial MHT study for GBM
thermotherapy. In addition, the combination of multiple therapies may patients [244], revealed that intratumoral injection of MNPs, followed
lead to increased toxicity and side effects, necessitating careful moni­ by MHT irradiation at 49.5 ◦ C, led to an increase in macrophages within
toring and management. Further, the cost and availability of these the tumor. This finding emphasized the impact of MHT on immune

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

Fig. 16. Metastasis and recurrence inhibition of 4T1 tumors via systemic immune effects induced by JQ1/IONAs with AMF. (A) Schematic illustration of treatments
in lung metastasis model. (B, C) Recurrent tumor growth curves and recurrence rates in various groups. (D–F) Representative lung photographs. (G) Survival curves
of mice after different treatments in 45 days. Reproduced with permission [241]. Copyright 2023, Elsevier.

response, suggesting potential benefits for patient treatment outcomes. 8. Clinical translation challenges and future research priorities
Following this, multiple studies in animal models have also substanti­ of MHT in tumor treatment
ated the finding that MHT can stimulate the immune response in pa­
tients [203,245,246]. Consequently, an extensive array of research into MHT demonstrates significant potential in tumor therapy, yet its
the fusion of MHT with tumor immunotherapy has been progressively clinical translation faces multiple bottlenecks, including biosafety of
conducted. MNPs, targeted delivery efficiency, precise control, device development,
and regulatory/ethical challenges. Future research should focus on the

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L. Xiong et al. Materials Today Bio 33 (2025) 102070

development of novel nanomaterials, optimization of combination 8.2. Future research priorities of MHT
therapies, construction of intelligent systems, and interdisciplinary
collaboration to overcome technical and institutional barriers [247]. 8.2.1. Development of novel MNPs
Multifunctional NPs: Integration of diagnostic (MRI, photoacoustic
8.1. Technical bottlenecks in MHT clinical translation imaging) and therapeutic functions into a single nanoplatform enables
precise tumor localization, real-time monitoring, and personalized
8.1.1. Biosafety of MNPs therapy. For example, fluorescent dye-loaded nanoparticles can delin­
Toxicity assessment: the evaluation of in vivo toxicity of MNPs re­ eate tumor boundaries pre-treatment, while MRI-guided temperature
mains a critical barrier. Current studies indicate that certain NPs (e.g., monitoring enhances precision. Biodegradable NPs: Materials like PLGA
unmodified IONPs) may induce oxidative stress, elevate ROS levels and offer enhanced biosafety by degrading into harmless metabolites post-
cause mitochondrial and DNA damage in normal tissues. Surface charge, treatment. Tailoring degradation rates can optimize magnetic perfor­
particle size, and morphology also influence toxicity. For example, mance and therapeutic outcomes.
nanoparticles <10 nm exhibit higher membrane permeability,
increasing interactions with intracellular biomolecules and toxicity 8.2.2. Intelligent MHT systems
risks. However, existing toxicity assessments rely on in vitro or short- Real-time monitoring and feedback: Closed-loop systems integrating
term animal models, which fail to accurately simulate human physi­ microsensors, wireless modules, and machine learning algorithms
ology, leading to discrepancies between preclinical and clinical out­ enable dynamic temperature regulation. For instance, fiber-optic sen­
comes. Long-term biological effects: The chronic retention and risks of sors combined with predictive algorithms adjust magnetic parameters to
MNPs in vivo remain understudied. Preclinical data suggest prolonged maintain optimal thermal ranges [248]. Personalized treatment: Artifi­
accumulation in reticuloendothelial system (RES) organs (e.g., liver, cial intelligence-driven analysis of tumor genomics, imaging, and clin­
spleen), potentially disrupting organ function. NPs aggregation, degra­ ical data facilitates tailored therapy [8]. Digital twin technology can
dation, or surface alterations, along with unknown biosafety profiles of simulate patient-specific tumor responses, guiding clinical decisions
degradation products (e.g., iron overload from slow degradation), and through predictive modeling.
further complicate clinical applications. The lack of long-term follow-up
data and monitoring tools poses significant safety concerns. 9. Conclusion and prospects

8.1.2. Targeting and delivery efficiency MHT has emerged as a key strategy in precision oncology due to its
Targeting strategies: current approaches (active/passive targeting) non-invasiveness, deep tissue penetration, and synergistic interaction
face limitations. Active targeting suffers from ligand-antigen binding with the TME, capable of inducing multiple cell death pathways such as
specificity issues and immunogenicity, while passive targeting is hin­ apoptosis, ferroptosis, and pyroptosis. Compared with traditional HT,
dered by tumor vascular heterogeneity, resulting in poor penetration MHT enables localized thermal control while minimizing non-target
into deep tumor regions and uneven cellular coverage. Delivery opti­ tissue damage. Nanomaterials are classified into inorganic (e.g., iron
mization: structural designs (core-shell, hollow architectures) and sur­ oxides, cobalt ferrites), organic (liposomes, polymers), and hybrid sys­
face modifications (PEGylation, thermoresponsive coatings) aim to tems, with heating efficiency, biodistribution, and surface functionali­
improve pharmacokinetics. However, complex designs increase pro­ zation (e.g., PEGylation, targeted ligand modification) being critical to
duction costs, surface modifications may compromise magnetic perfor­ enhancing efficacy and safety. Current research emphasizes multimodal
mance, and dynamic tumor microenvironments (pH, enzymatic activity) combination strategies to enhance antitumor efficacy through syner­
destabilize nanoparticle delivery, limiting efficiency. gistic mechanisms. However, the complexity of treatments and incon­
sistent protocols may lead to unpredictable synergistic toxicity,
8.1.3. Precision control in MHT necessitating a dose-time-intensity optimization framework to balance
Temperature regulation: Precise thermal control is critical to avoid efficacy and safety.
normal tissue damage. Current monitoring techniques (magnetic reso­ Future directions for clinical translation involve interdisciplinary
nance thermometry, infrared thermography) lack spatial resolution and material innovation and intelligent system construction, requiring
real-time feedback. Tumor heterogeneity in thermal conductivity and strengthened integration of materials science, immunology, and engi­
blood flow exacerbates temperature inhomogeneity. Suboptimal tem­ neering to develop smart responsive nanoplatforms, compact AMF
peratures either fail to kill tumor cells or damage healthy tissues. generators compatible with MRI thermometry and adaptive parameter
Treatment depth and coverage: Although MHT holds promise for deep- adjustment. Designing biomimetic carriers (e.g., exosome-modified
seated tumors, clinical application requires optimization of magnetic magnetic nanoparticles) to enhance tumor affinity, combined with
field penetration and NPs distribution. Limited penetration depth of self-regulating thermoresponsive materials to prevent overheating.
AMF and uneven NPs dispersion lead to incomplete tumor ablation. Meanwhile, materials can carry multiple drugs, such as chemothera­
Irregular tumor morphology further complicates precise treatment. peutic agents, immune adjuvants, and even tumor gene intervention
factors, to achieve multi-faceted synergistic therapy. Additionally, the
8.1.4. Technical limitations of MHT devices platform should incorporate machine learning guidance to dynamically
Existing MHT devices face challenges in magnetic field uniformity, optimize AMF parameters and nanomaterial dosages through AI algo­
excessive size, operational complexity, and high costs. Clinical-grade rithms. Evaluating multicenter phase I/II clinical trials to summarize the
systems struggle to maintain uniform heating in large treatment areas, long-term biodistribution and metabolic pathways of materials, and
while inefficient cooling systems increase thermal injury risks. High establishing standardized efficacy indicators, so as to address the multi-
costs also hinder widespread adoption in resource-limited settings. faceted research bottlenecks of MHT materials in safety, standardiza­
tion, and efficiency.
8.1.5. Regulatory and ethical challenges Through multidisciplinary collaboration, MHT has transformative
MHT confronts undefined regulatory frameworks and ethical di­ potential to evolve from an experimental platform to a clinical mainstay,
lemmas. Safety and efficacy standards for MNPs remain incomplete, thereby becoming the fourth pillar of cancer treatment alongside sur­
complicating regulatory classification. Ethical issues include insufficient gery, radiotherapy, and chemotherapy. This paradigm shift could
patient awareness of long-term risks (information asymmetry in redefine the treatment landscape for malignancies refractory to con­
informed consent) and the absence of standardized dosing and protocols ventional therapies.
in clinical trials, potentially compromising patient rights.

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