Biomedicine & Pharmacotherapy 170 (2024) 115992

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Nanovaccines: An effective therapeutic approach for cancer therapy

Sangiliyandi Gurunathan a, *, Pratheep Thangaraj a, Lin Wang b, Qilong Cao b, Jin-Hoi Kim c, *
a
Department of Biotechnology, Rathinam College of Arts and Science, Eachanari, Coimbatore 641 021, Tamil Nadu, India
b
Research and Development Department, Qingdao Haier Biotech Co., Ltd., Qingdao, China
c
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Republic of Korea

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

Keywords: Cancer vaccines hold considerable promise for the immunotherapy of solid tumors. Nanomedicine offers several
Cancer strategies for enhancing vaccine effectiveness. In particular, molecular or (sub) cellular vaccines can be delivered
Immunotherapy to the target lymphoid tissues and cells by nanocarriers and nanoplatforms to increase the potency and durability
Nanovaccine
of antitumor immunity and minimize negative side effects. Nanovaccines use nanoparticles (NPs) as carriers and/
Nanocarrier
or adjuvants, offering the advantages of optimal nanoscale size, high stability, ample antigen loading, high
Membrane vesicle
Tumor vaccine immunogenicity, tunable antigen presentation, increased retention in lymph nodes, and immunity promotion. To
induce antitumor immunity, cancer vaccines rely on tumor antigens, which are administered in the form of entire
cells, peptides, nucleic acids, extracellular vesicles (EVs), or cell membrane–encapsulated NPs. Ideal cancer
vaccines stimulate both humoral and cellular immunity while overcoming tumor-induced immune suppression.
Herein, we review the key properties of nanovaccines for cancer immunotherapy and highlight the recent ad­
vances in their development based on the structure and composition of various (including synthetic and semi
(biogenic) nanocarriers. Moreover, we discuss tumor cell–derived vaccines (including those based on whole-
tumor-cell components, EVs, cell membrane–encapsulated NPs, and hybrid membrane–coated NPs), nano­
vaccine action mechanisms, and the challenges of immunocancer therapy and their translation to clinical
applications.

1. Introduction patient’s immune system to recognize and eliminate cancer cells [6,7]
and can induce specific antitumor immune responses resulting in the
By 2023, the number of new cancer cases worldwide is expected to targeted killing of tumor cells with few adverse effects and elicit an
reach 18.1 million (9.3 million men and 8.8 million women) [1–4]. Most immune memory offering long-term protection against tumor recur­
cancer patients receive traditional treatments, such as surgery, chemo­ rence [8–11]. Chemically produced vaccines are simple to prepare and
therapy, radiation therapy, immunotherapy, targeted therapy, or hor­ usually safe to deliver; however, subunit chemical-mediated vaccines
mone therapy. Chemotherapy has numerous drawbacks, such as lack of frequently have poor immunogenicity and produce only transient im­
specificity, cytotoxicity, drug resistance development, and stem-like cell mune responses. To overcome these difficulties, nanoengineering
formation. Nanomedicine has led to the development of novel strategies methods have been used in the development of subunit vaccines with
for cancer therapy, including cancer diagnosis, prevention, and treat­ delivery vehicles. Compared to subunit vaccines, nanovaccines have
ment. Immunotherapy, one of the numerous cancer treatments, trains numerous advantages, such as the simultaneous delivery of antigens and
the immune cells to selectively identify and eradicate cancer cells. Based adjuvants, easy phagocytosis and processing by antigen-presenting cells
on immunological memory, the immune system can offer long-term (APCs), promotion of adaptive immune responses, ease of nanoparticle
defense against tumor recurrence and metastasis. The sustained sur­ (NP) surface modification with targeting ligands, and polyvalent pre­
vival benefit for a subgroup of patients, which results in complete tumor sentation of antigens on the nanovaccine surface [12,13]. In particular,
remission in some circumstances, has brought attention to the clinical the modification of the NP surface with target ligands enables specific
success of cancer immunotherapy [5]. targeting to lymphoid tissues and APCs for precise immunomodulation,
Cancer vaccination is an appealing supplement or replacement of while the polyvalent presentation of antigens on the nanovaccine sur­
standard cancer therapies. Cancer vaccines are designed to train the faceallows B-cell receptors to be cross-linked for enhanced humoral

* Corresponding authors.
E-mail addresses: sangiliyandi.re@rathinam.in (S. Gurunathan), jhkim541@konkuk.ac.kr (J.-H. Kim).

https://doi.org/10.1016/j.biopha.2023.115992
Received 26 August 2023; Received in revised form 23 November 2023; Accepted 6 December 2023
Available online 9 December 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

immune responses. platforms and nanoengineering technologies, a new research area

Nanoengineering offers numerous benefits, such as serum stability, striving to realize the full therapeutic potential of immunotherapy has
high loading capacity, customized surface chemistry, controlled release, emerged as a result of advancements in nanomedicine and immuno­
and naked formulations of diverse bioplatforms with customizable sizes therapy. Preclinical investigations have shown that nano­
[14,15]. Nanovaccines containing tumor antigens have great bioavail­ immunotherapy can mitigate the drawbacks of existing cancer
ability and pharmacokinetic qualities, which are crucial for inducing a immunotherapies [40]. Herein, we review the recent advances in the
sufficiently potent and durable anticancer immune response [16]. Ac­ development of cancer nanovaccines, including vaccine composition,
cording to Hu et al. [17], numerous NPs have been used to improve nanocarrier type (e.g., synthetic, biogenic, and semibiogenic), and
innate/adaptive immune responses and transport antigens to vital cell nanovaccine type and platform. Furthermore, we highlight the recent
types. Nanovaccines can intrinsically improve cross presentation by advances in tumor cell–derived vaccines (including whole-tumor-cell
enhancing antigen uptake and internalization by APCs and facilitating components, extracellular vesicles (EVs), cell membrane–encapsulated
the maturation of dendritic cells (DCs), thereby inducing antitumor NPs, and hybrid membrane–coated NP vaccines)for cancer immuno­
immune responses [18–20]. NPs greatly improve the stability of nano­ therapy and discuss nanovaccine action mechanisms.
vaccines, protecting antigens from degradation by intracellular pro­
teases and sustaining antigen release [21,22]. 2. Nanovaccine composition
The size, surface charge, and surface functionalization of the tar­
geting molecules determine the endocytic internalization pathways of Subunit vaccinations alone cannot protect from lethal infections
NP-supplied antigens. These characteristics facilitate the transportation because of their insufficient immune activation and short duration of
of antigens to APCs for presentation. Cationic NPs are more rapidly protective immunity [41]. NP-based delivery vehicles, such as viro­
internalized by APCs and typically promote intracellular trafficking by somes, liposomes, micelles, microemulsions, dendrimers, and nanogels,
endosomal escape [23]. Antigens adsorbed on cationic dendrimer NPs can potentially be used to overcome the limitations of conventional
are more efficiently delivered to DCs while activating them and causing vaccination adjuvants [38]. Nanovaccines can improve the transport of
them to secrete cytokines, such as IL-1β and IL-12 [24]. DCs are essential antigens and adjuvants, antigen presentation by APCs, promotion of
for the coordination of the innate and adaptive immune systems through innate immune responses, and robust effector T-cell responses [42].
the absorption, processing, and presentation of epitopes to naive T cells Thus, the development of potent immunotherapeutic formulations for
and have mannose receptors on their surface, which facilitate antigen human malignancies can greatly benefit from the use of nanovaccines
internalization by mannosylation. This process improves the activation [43], which typically contain antigens, adjuvants, and nanocarriers
of T-cell (specifically CD4 + and CD8 +) responses [25]. During (Fig. 1).
cross-presentation, DCs can also digest antigens and present them via the
major histocompatibility complex (MHC) I pathway, activating the CD8 2.1. Antigens
+ T-cell response [26,27]. In this case, the cytosolic route is responsible
for cross-presentation. Proteasomes break down the foreign antigens in Tumor antigens, which are divided into TSAs (present only in ma­
the cytosol [27]. Nanovaccines enable cross presentation enhancement lignant cells) and tumor-associated antigens (TAAs; produced at lower
and intracellular antigen deliverymodulation. Numerous NP forms, such levels in both cancerous and noncancerous cells), can be displayed on
as lipid, polymeric, and inorganic NPs, can effectively stimulate the the surface of tumor cells to activate T lymphocytes via MHC-I [44].
growth of CD8 + T cells by antigen cross-presentation. With effective Endogenous cancer antigens cannot elicit immunologically significant
crosspriming and Th1 immune responses, a custom-made polymeric responses because of their immune evasion and immunosuppressive
micro needle containing encapsulated antigens was successfully used to mechanisms. Exogenous tumor-associated antigens induce
target Langerhans cells [28–30]. antigen-specific immune responses against tumor cells during cancer
Carson et al. [31] reported a nanovaccine design based on diblock immunotherapy and are therefore useful for the development of cancer
copolymers facilitating the endosomal escape of the associated vaccine vaccines [5]. TAAs are expressed by both normal and tumor cells in
cargo to the cytosol. In this study, endosomolytic nanoparticles pro­ various cancer types [44]. HER-2/neu, melanoma-associated antigen
moted the cytosolic co-delivery of protein antigens (which facilitated (MAGE)-A, TTK protein kinase (TTK), LAGE-1, and the gene encoding
antigen cross-presentation, co-stimulatory molecule expression, and NY-ESO(New York esophageal squamous cell carcinoma)− 1 are the
cytokine production) and enhanced the magnitude and functionality of most important TAAs used in cancer vaccines [13,44,45].
CD8 + T-cell responses relative to anantigen–polyIC mixture to inhibit
tumor growth in a mouse tumor model. 2.2. Adjuvants
Tumor immunotherapy aims to stimulate the immune system to
generate an antitumor immune response preventingtumor emergence, Adjuvants are used to induce robust responses in individuals
growth, and recurrence [32,33]. Common immunotherapeutic tech­ receiving vaccines and can activate the immune system and amplify
niques include the use of monoclonal antibodies [34], immune check­ immunological and direct immune reactions [46]. These properties are
point blockers [35], lytic virus therapy [36], and tumor vaccines [14]. crucial for subunit antigens, which are typically weakly immunogenic.
APCs and tumor-specific T lymphocytes can be stimulated by tumor Based on their principal action mechanisms, adjuvants are generally
vaccines through the effective delivery of tumor-specific antigens (TSAs) divided into (a) vaccine delivery systems, such as mineral salts, emul­
to induce local tumor regression and metastatic lesion elimination [37]. sions, liposomes, and virosomes, which deliver in a more efficient way
TSAs need to be absorbed by DCs for optimum T-cell activation to trigger and control the release and storage of antigens [47–49]; and (b)
tumor immune responses using tumor vaccines [38]. The production of immunostimulatory molecular adjuvants, including toll-like receptor
tumor vaccines requires a broad variety of tumor antigens and (TLR) agonists, STING agonists, costimulatory ligands, and cytokines
high-performance delivery systems, which should be enhanced to [50,51], which activate immune cells such as APCs to potentiate
maximize tumor immunogenicity [26]. Although tumor cell–derived antigen-specific immune responses. Adjuvants and antigens can be
vaccines contain numerous antigens, their capacity to promote tumor shielded from degradation by proteases, phosphatases, and nucleases
immunogenicity requires considerable optimization, e.g., through ge­ when loaded into NPs [52]. Adjuvants can cause systemic toxicity
netic and chemical engineering [39]. Even though immunotherapy has manifesting as fever, diarrhea, nausea, and tiredness in vaccine re­
become a new standard pillar for cancer treatment, it often benefits only cipients [53]. Consequently, organs can be shielded from systemic
a small percentage of patients and poses the problem of immunotoxicity, toxicity through the encapsulation of adjuvants and antigen-utilizing
which restricts potential therapeutic applications. With the help of NP NPs. Nanoencapsulation can potentially be used to trigger and activate

2
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Fig. 1. Nanovaccine structure, composition, type, and functions. Following the administration of the nanovaccine and antigen and adjuvant delivery to lymphoid
tissues, the antigens are ingested by dendritic cells (DCs) to induce their maturation and activation. The DCs transfer the antigens to CD8 + T cells and activate their
proliferation using major histocompatibility complexes (MHCs). Finally, antigen-specific T lymphocytes penetrate and kill cancer cells in the TME (created with
Biorender.com).

immunological responses via slow antigen release [53]. immune cells in lymphoid organs or other immune target locations
distant from and independent of tumors to induce systemic antitumor
immunity and therefore avoid the hurdles associated with tumor tar­
2.3. Nanocarriers
geting. Additionally, immune cells have a remarkable capacity to pass
through bodily defenses that NPs typically have difficulty penetrating
Nanocarriers are the most important components of nanovaccines,
(such as the blood–brain barrier and tumor vasculature), enabling the
offering several advantages owing to their high surface area and surface-
indirect but potentially more effective therapeutic action of nanocarriers
to-volume ratio, efficient loading, and capacity for a variety of cargoes,
through the manipulation of immune cells [66]. To achieve high anti­
including small molecules, large proteins, and nucleic acids. The
cancer activity through diverse therapeutic actions, nanocarrier-based
comparatively large nanosize limits efflux transit from cells and thus
immunotherapy can be used to target immune cells in combination
enables effective interactions with the cell membrane to further enhance
with direct tumor regulation. Numerous nanomaterials have been
cellular uptake and promotein-cell accumulation. Additionally, NP for­
investigated for the delivery of vaccines in cancer immunotherapy, and
mation can enhance the solubility, in vivo stability, systemic circulation,
different nanocarriers have been used in immunotherapy and as cancer
and biodistribution of payload medications in the body [54,55]. Nano­
vaccines. Nanocarriers are classified into (semi)biogenic, (semi)syn­
carriers can protect nucleic acids from enzymatic degradation, extend in
thetic, and self-adjuvant (Fig. 2).
vivo circulation, and enhance targeted delivery and cellular absorption
for effective transcriptional regulation. Moreover, nanocarriers can be
3. Nanocarrier types
actively targeted by functionalization with tumor affinity ligands or
passively targeted by increased permeation and retention effects and can
3.1. Biogenic nanocarriers
efficiently accumulate in lymphoid organs and other immune target sites
[56–60]. For example, NP formation was shown to enhancethe local
Biogenic nanocarriers, i.e., nanomaterials produced by organisms,
transport of immunoadjuvants into peripheral lymphoid organs while
exhibit high potential biocompatibility, high biodegradability, and low
limiting systemic distribution, maximizing immunological activity, and
toxicity. Bacterial outer membrane vesicles (OMVs) and exosomes are
minimizing systemic immunotoxicity [61,62]. Additionally, the
prominent examples of biogenic nanocarriers. EVs, including exosomes,
administration of antibodies via NPs was reported to activate and target
microvesicles, ectosomes, oncosomes, and apoptotic bodies, are lipid-
APCs and T cells and demonstrate therapeutic advantages in a variety of
based vesicles containing lipids, proteins, and nucleic acids generated
tumor types, including melanoma, nonsmall cell lung cancer, renal
by various cells and released into the surrounding environment [67].
cancer, and Hodgkin’s lymphoma [63,64].
Commensal and pathogenic bacteria create EVs that are classified as
To circumvent the systemic and local barriers preventing tumor
either micro vesicles (MVs) or OMVs, depending on whether they are
infiltration and the subsequent cellular uptake of systemically admin­
produced by gram-positive or -negative bacteria, respectively. EVs
istered NPs, nanocarriers can be developed to specifically target and
produced by bacteria can influence the human immune system and
destroy tumors under the traditional nanomedicine regime [65]. How­
induce pro-inflammatory reactions [68]. Probiotic-derived systems
ever, when used for immunotherapy, nanocarriers can be directed to

3
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Fig. 2. Different types of nanocarriers (created with Biorender.com).

typically modulate the immune system. antigens to APCs and lymph nodes, drawing considerable interest in
cancer immunotherapy. From a safety perspective, OMVs are non-
replicating particles that are safe and free of live bacterial cells. OMVs
3.2. OMVs carrying RNA, DNA, endotoxins, proteins, and virulence compounds are
representative examples of biochemical signaling involving the trans­
OMVs, i.e., nanosized proteoliposomes produced from the outer port of bacterial OMVs (Fig. 3). Given that bacterial OMVs contain
membranes of gram-negative bacteria, have average sizes of 50–300 nm immunostimulating danger signals such as lipopolysaccharides,
and are therefore suitable carriers for the intracellular transport of

Fig. 3. Composition and advantages of outer membrane vesicles(OMVs) and exosomes as nanocarriers.(Left panel) OMVs are nanoparticles (NPs) containing
bioactive molecules, e.g., lipopolysaccharides, porins, flagellin, outer membrane proteins, lipoproteins, toxins, enzymes, periplasmic proteins, cytoplasmic proteins,
peptidoglycans, metabolites, DNA, and RNA. Consequently, OMVs can be rapidly recognized and absorbed by DCs and can activate multiple innate immune signaling
pathways, thereby exerting a natural adjuvant effect and decreasing the degradation of loaded antigens.(Right panel) Exosomes are NPswith a lipid bilayer mem­
branous structure containing various functional constituents (such asproteins, lipids, microRNA (miRNA), lncRNA) and other components (such as nucleic acids,
signaling molecules, and transporters). The exosomal components play a crucial role in cancer progression and act as potential biomarkers (created with Bio­
render.com).

4
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

lipoproteins, and flagellin, which stimulate TLR4 and TLR5, respec­ exosomes. Depending on the cell source, exosomes may be employed for
tively, they can be used as carriers and adjuvants for vaccine develop­ the immunotherapy of autoimmune or cancerous illnesses [84]. For
ment [69,70]. The development of OMV-based tumor nanovaccines instance, tumor-derived exosomes carrying MHC/epitope molecular
depends on various factors, including the type of strain, OMV hetero­ complexes for recognition by T-cell receptors for T-cell activation are
geneity, efficacy of tumor antigen loading, immunogenicity, safety, and useful in treating cancer [85]. Exosomes created by DCs are packed with
suitability for mass production [71]. receptors and other elements necessary for T-cell activation and antigen
OMVs have been used to produce vaccines against cancer and bac­ presentation [86]. Given their ability to provide exogenous vaccines,
teria and can be loaded with TLR agonists and antitumor cytokines in exosomes are also useful in cancer immunotherapy.
cancer vaccines to extend antitumor immune responses and eradicate
tumor cells with minimal negative effects [72]. The maturity of these 3.4. Role of membrane vesicles in immune modulation
APCs and survival of antigen cross-presentation to CD8 + T cells can be
achieved by engineering OMVs generated by programming DCs [73]. In Membrane vesicles have been extensively studied and used because
a recent study, cytolysin A was fused with cancer antigens on the surface of the potential benefits of the corresponding vaccines used to elicit
of OMVs, and the antigen display process was accelerated using a immune responses against tumors [87]. The function of membrane
plug-and-display system with tag/catcher protein pairs. OMVs embel­ vesicles in immune regulation can be attributed to the presentation or
lished with several protein catchers can simultaneously express a variety transfer of antigenic peptides (TSAs orTAAs); delivery of adjuvants,
of tumor antigens to synergistically induce anticancer immune re­ immunomodulatory molecules, or cytosolic DNA; gene expression
sponses. Engineered OMVs with multiple tumor antigens were used to manipulation by miRNA or plasmids; and induction of favorable
prevent melanoma-induced lung metastasis and subcutaneous colorectal signaling pathways by ligands expressed on the vesicle surface. In terms
cancer growth [74]. Several clinical experiments are now being con­ of immune-based mechanisms, membrane vesicle vaccines generally
ducted on the use of bacterial OMVs to treat human cancers. Different induce the activation and maturation of DCs, stimulation of T cells, and
immunostimulatory elements found in OMVs aid their recognition and immunological memory enhancement, all of which contribute to the
absorption and trigger immune responses. OMVs can infiltrate or bind to effectiveness of tumor suppression and prolonged survival in numerous
tumor sites because of their nanosize, which allows them to exert EPR biological tumor models (Fig. 4). OMVs interact with various immune
effects to increase local immunity [75]. cells, including DCs, and stimulate both innate and adaptive immunity,
An in vivo study demonstrated that intravenously injected OMVs are thus holding promise for the development of endogenous vaccines.
stored at tumor sites and elicitsubstantial antitumor immune responses OMVs include various pathogen-associated molecular patterns (PAMPs),
to eliminate tumors. Interestingly, the OMV-induced antitumor immune such as lipoproteins, lipopolysaccharides, and pathogenic DNA frag­
response caused immunological responses in mice through the modu­ ments, which activate TLRs and NOD-like receptors (NLRs) to
lation of IFN-γ [76]. The co-administration of OMVs and chemothera­ strengthen the innate immune system of the host. OMVs with lower
peutic drugs led to a better antitumor response. For example, OMVs endotoxicity exhibit better mucosal adjuvant properties. Although the
loaded with polyethylene glycol and Arg-Gly-Asp peptide, a host immune system is the first line of defense against any illness,
tumor-targeting ligand, enhanced blood circulation and tumor-targeting overreactions may harm dormant tissue. Consequently, a mechanism for
properties [77]. Tegafur-coated OMVs decrease the potency suppressing negative immune reactions is required. OMVs provide
ofmyeloid-derived suppressor cells and other immunosuppressive cells, complete protection because they carry pathogen antigens in addition to
rendering them more susceptible to T lymphocytes. These OMV-coated exhibiting adjuvant properties [88].
NPs exhibited antitumor properties that activated the host immune
system. Using the EPR effect and active targeting provided by the 3.5. Semibiogenic nanocarriers
Arg-Gly-Asp peptide, OVMs were systemically injected to promote the
accumulation of particles in tumors [77]. Semibiogenic nanocarriers, whichhave biogenic and synthetic com­
ponents, exhibit the benefits of excellent biocompatibility, low toxicity,
3.3. Exosomes simple and reproducible large-scale manufacturing, and other notable
engineering qualities and are classified into cell membrane–coated
Exosomes are nanovesicles with sizes of 30–150 nm. The phospho­ nanocarriers, virus-like particles (VLPs), and endogenous protein–based
lipid bilayer structures of exosomes enable stable drug transport, extend nanocarriers [89]. Several studies have shown the potential of coated
drughalf-life during delivery, and protect drugs from enzymatic degra­ nanocarriers as biomimetic platforms for drug delivery. The desired cell
dation. Additionally, exosome membranes can easily bind to target cells membrane can be extracted and used as acoating for the NP surface or
and thus increase the bioavailability of the loaded drugs. Compared to building block for nanocarrier construction. As a platform for cancer
conventional drug carriers, such as liposomes, exosomes have poor nanovaccines, cancer cell membrane (CCM)-coated NPs can carrya wide
immunogenicity and toxicity profiles. The small size of exosomes allows range of CCM antigens [90,91]. Furthermore, a potent anticancer im­
them to move throughout the tumor tissue, extravasate into tumor ar­ mune response similar to those observed for bacterial infections can be
teries, and thus effectively treat tumors. Therefore, exosomes can produced by combining adjuvants, cell membrane antigens, and specific
overcome various physiological obstacles and increase drug efficacy ligands.
[78,79], thus holding considerable promise for effective immuno­ Cell membrane camouflage–based nanovaccines have a wide range
therapy and vaccine administration. of clinical applications and enable the simple fabrication of adjuvants
Depending on their biological source and the clinical situation, and cell membrane materials from patientcancer cells. Collectively,
exosomes can either suppress or boost the immune system and can these studies show that NPs with cell membrane coatings have great
therefore influence the immunotherapy of tumors and autoimmune potential as nanovaccines. Self-assembled structural proteins(VLPs) are
disorders. Exosomes and their contents, such as exosomal microRNAs typical examples of semisynthetic nanocarriers that can be potentially
(miRNAs), can be used as predictive tools to assess the disease stage and used as cancer nanovaccines and offer the benefit of simple antigen
thus facilitate diagnosis and treatment [80]. For example, bovine customization. Despite being structurally similar to viruses, VLPs lack
milk–derived exosomes can be used as nanocarriers to deliver chemo­ the genetic material of the latter and are therefore noninfectious.
therapeutic/chemopreventive agents in lung cancer treatment [81]. Repeated antigenic structures can be designed to effectively activate the
Exosomes loaded with miRNAs (e.g., miR-146b) can be used as nano­ immune system. Antigens built into VLP-based nanovaccines can
carriers to treat gliomas [82]. Théry et al. [83] reported that various cell generate long-lasting adaptive immune responses because VLPs are
types, including T cells, B cells, cancer cells, and APCs, produce easily taken up by APCs [92]. Moreover, VLPs are prospective tools for

5
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Fig. 4. Role of membrane vesicles as tumor vaccines in immune modulation. Membrane vesicles containing stimulators can activate innate and acquired anticancer
immune responses. The M2 to M1 phenotype polarization is induced by changes in the interactions of vesicles with macrophages. To further activate CD8 + T cells
and trigger a cytotoxic T-lymphocyte antitumor response, DCs may deliver vesicles containing certain antigens or peptides. Tregs, which are immunosuppressive T
cells commonly found in the tumor microenvironment, are downregulated by CD4 + T cells during the antigen presentation phase to activate long-term memory
immunity (created with Biorender.com).

nanovaccine design and production owing to the ease of their modifi­ effectively induce postvaccination immune responses, cancer vaccines
cation through genetic engineering and the feasibility of designing must be delivered to lymphoid tissues and APCs. In this context, the use
surface antigen expression. Given their ability to acquire VLPs and of assembled and appropriately sized protein–drug nanocomplexes en­
generate strong long-lasting adaptive immune responses, repeating ables efficient lymphatic drainage and intracellular uptake. Further­
antigenic structures built into VLP-based nanovaccines can effectively more, the highly expressed neonatal Fc receptor on APCs can endocytose
activate the immune system [92]. Several antigens were produced on albumin and facilitate the distribution of nanocomplexes containing
the VLP surface using the G protein of the vesicular stomatitis virus as a vaccines and albumin within cells. As an endogenous drug carrier of­
model [93,94]. fering the benefits of a long half-life in the human body (20 d),
Another method for the antigen modification of VLPs with bifunc­ simplicity, excellent quality, and adherence to good manufacturing
tional crosslinkers is chemical conjugation [95]. According to Schneider practice (GMP), albumin is well suited for the administration of radio­
et al. [96], VLPs displaying tumor antigens can trigger potent immune nucleotides, molecular vaccines, and anticancer medications and is an
responses and successfully cure cancer. For instance, a vaccine against advantageous alternative to synthetic nanomaterials [39,99,100]. Evans
cervical cancer was developed using a vector technology based on blue–conjugated molecular vaccines for albumin-binding agents (Albi­
baculovirus expression to create antigens against HPV-16 and HPV-18 Vax) self-assemble in vivo from endogenous albumin and AlbiVax.
L1 VLPs. Consequently, these HPV-16 and HPV-18 L1 VLPs elicited Albumin/AlbiVax can generate peripheral antigen-specific CD8 + cy­
immune responses, enhancing vaccine efficacy in cervical cancer pa­ totoxic T cells in B16F10, MC38, and EG7. OVA tumors with a memory
tients [97]. Taken together, these experiments show that VLPs can be that is approximately 10times greater than that of incomplete Freund’s
effective cancer nanovaccines. adjuvant-emulsifying vaccines [101].

3.6. Endogenous protein–based nanocarriers 3.7. Cell membrane–coated nanocarriers

Synthetic chemistry and other physicochemical techniques play an Cell membrane–coated nanocarriers hold considerable promise for
important role in the safe and precise delivery of pharmaceutical for­ biological applications. Depending on the type of the employed cell
mulations. As the research paradigm has increasingly shifted toward membrane, the resulting biomimetic nanoformulation has several
green techniques, several biopolymer-based nanocarriers have been properties that are typically associated with the source cell, including
identified as promising nanomedicine tools. These nanocarriers have improved biocompatibility, immune evasion, and tumor targeting. CNPs
been created to address the drawbacks of traditional drug delivery sys­ feature a synthetic nanoparticulate core covered by a layer of naturally
tems, which often result in severe side effects, particularly when they are derived cell membranes and therefore efficiently operate in complex
nonspecific and have negative effects on healthy cells. Protein-based biological environments. Cell membrane coating is more efficient in
nanocarriers may help avoid unfavorable immunological reactions and producing multifunctional and multiantigenic NPs than conventional
are mostly nontoxic, biodegradable, and even inexpensive [98]. To functionalization techniques [102].

6
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Cell membrane camouflage is another nanocarrier type used as a mice with lymphoma was shown to increase the accumulation of
bioinspired platform for medication delivery. After the target cell doxorubicin in the TME to encourage tumor cell apoptosis and auto­
membrane has been removed, as in the case of cancer cells, itis coated phagy, stimulating immunogenic cell death and autophagy-mediated T-
onto NP surfaces or used as a building block to create nanocarriers [90, helper 1–type immune responses. Additionally, the co-delivery of CpG
91]. Additionally, NPs coated with the membranes of patient tumor cells with doxorubicin promoted antitumor responses, decelerated tumor
can transport tumor cell membrane antigens to APCs and, ultimately, to growth, and increased animal longevity [117]. Studies on animal
effector cells [103]. This technique enables the engineering of cell models demonstrated that TAAs conjugated to certain mineral NPs can
membrane molecules, adjuvants, and NPs coated with tumor cell detect target antigens and inhibit tumor growth [114,118]. These vac­
membranes with adjuvants and enables the effective use of specific li­ cines can strongly activate the immune system to produce antibodies
gands as nanovaccines to treat cancer. For example, emtansine has been and induce cellular immunological responses because the AuNPs nu­
successfully used as an anticancer drug to limit lung metastasis in cleus allows SNAs to enter cells without the need for delivery vehicles or
metastatic 4T1 breast cancer cells using pH-sensitive liposomes covered transfection chemicals [117].
with a macrophage membrane [104].
3.9. Adjuvants and self-adjuvanted carriers
3.8. Synthetic nanocarriers
Based on their immunological concepts, adjuvants are categorized
Numerous synthetic nanocarriers, e.g., liposomes, polymer-based into those (1) facilitating antigen uptake, transport, and presentation by
NPs, and inorganic materials, have been investigated as delivery sys­ APCs; (2) enabling antigen depot formation and prolonged antigen de­
tems for cancer immunotherapies. Liposomes exhibit high biodegrad­ livery; (3) targeting the pattern recognition receptor (PRR) to elicit an
ability because of their phospholipid bilayer structures. Compared to innate immune response; and (4) encouraging APC polarization, T-cell
naked antigens, those encapsulated in [105] or conjugated to [106] li­ differentiation, and B-cell activation [119]. PRR-targeting adjuvants,
posomes achieve a higher proliferation of antigen-specific CTLs. For including TLRs, NLRs, and RIG-I-like receptors (RLRs), have been
instance, plasmid DNA–carrying ovalbumin delivered by liposomes in­ extensively used. The corresponding targets include Pam3Cys (TLR2
duces a stronger CTL response than plasmid DNA alone [107]. Lipo­ ligand), poly(I:C) (TLR3 ligand), monophosphoryl lipid A (MPL; TLR4
somes can encapsulate and deliver mRNA, which considerably increases ligand), fagellin (TLR5 ligand), imiquimod (TLR7/8 ligand), and CpG
the immunogenicity of antigens compared to unformulated mRNA. For oligodeoxynucleotides (ODNs; TLR9 ligands) [120]. The toll-interleukin
example, in mRNA-encapsulated liposome vaccines [108], receptor (TIR)-domain-containing adaptor protein,
antigen-encoding synthetic mRNAs demonstrated greater safety than TIR-domain-containing adaptor-inducing interferon (TRIF), and
plasmid DNA. These results indicate that liposomes hold considerable TRIF-related adaptor molecule are among the adaptors employed by
promise as vaccine delivery vehicles. Bone marrow–derived DCs TLRs upon activation. These adaptors subsequently activate down­
cultured with cationic liposomes containing 1,2-dioleyl-3-trimethylam­ stream signal transduction, which, in turn, activates the corresponding
monium propane (DOTAP) were shown to enhance the expression of transcription factors to induce the secretion of chemokines and cyto­
co-stimulatory molecules, including CD80 and CD86,and increase the kines [121]. Similar to M8, adjuvants that target RLRs, such as M8, and
production of inflammatory chemokine genes and the maturation of adjuvants that target NLRs, such as muramyl dipeptides, activate the
CD11c+ cells [109,110]. innate immune response and have an immune-boosting effect[122].
Polymer NPs have been extensively studied asvaccine delivery Numerous diseases, including cancer, can be prevented and treated
agents for cancer immunotherapy, as exemplified by NPscomposed of with nanovaccines, which employ NPs as transporters and/or adjuvants.
poly(lactic-co-glycolic acid) (PLGA). The ester linkages in PLGA are Self-adjuvanted carriers offer the advantages of enhanced cross-
broken down in vivoto affordmetabolizable monomers, namely lactic presentation, signaling pathway targeting, and the biomimicking of
and glycolic acids. The size, solubility, and stability of the biodegradable the natural pathogen invasion process [123]. Some nanomaterials can
PLGA NPs can be precisely controlled. In addition, PEG or poly­ function as both potent immunoadjuvants and vaccine carriers [124].
etherimide can be combined with PLGA to create block copolymers that For example, chitosan, Al2O3 NPs, and polymethyl methacrylate NPs
can self-assemble into polymeric micelles and encapsulate hydrophobic (PMMNPs) are used as adjuvants because of their strong capacity to
payloads, such as certain peptide antigens [111]. Compared with com­ improve humoral and cellular immune responses while generating a
parable molecular antigens, antigen-loaded polymer nanovaccines are balanced Th1/Th2 response [125,126]. In mice administered with the
more effective in boosting T-cell responses [112]. According to another whole-virus HIV2 vaccination, PMMNPs exhibited a 100-fold more
study, poly(ethylenimine)-coated PLGA (ovalbumin) NPs generate an­ effective production of long-term antibody titers than traditional
tigen cross-presentation and powerful CD8 + cytotoxic T cell–mediated aluminum adjuvants [126]. Al2O3 NPs function as immunoadjuvants to
immune responses and may be used for effective anticancer immuno­ boost T-cell responses. Some NPs and adjuvants may worsen allergic
therapy [113]. reactions because of their immunostimulatory activity [127–129].
Inorganic materials have also been used as carriers in nanovaccine Tumor cells treated with hyaluronate-and trimethyl chitosan–coated
development, as inorganic nanocarriers can be easily functionalized and superparamagnetic iron oxide NPs loaded with hypoxia-inducible fac­
consumed by immune cells. Numerous inorganic NPs conjugated to tor-1-silencing small interfering RNA (siRNA) and E7046 (EP4 antago­
TAAs have been shown to reduce tumor growth in mouse tumor models nist) substantially inhibited cancer cell colony formation, proliferation,
in an antigen-specific manner[114,115]. Molecular vaccines can be migration, invasion, and angiogenesis [130]. Based on the origin of their
delivered via spherical nucleic acids (SNAs), which feature nucleic acid self-adjuvanting abilities, nanovaccines can be categorized into those (1)
cores decorated by gold NPs (AuNPs) [116]. The AuNPs allow the SNAs enhancing crosspresentation, which encourages exogenous cancer an­
to penetrate cells without additional delivery mechanisms or trans­ tigens to be taken up by DCs and crosspresented for CD8 + T-cell
fection agents. Compared with the corresponding molecular vaccines, priming; (2) targeting the signaling pathways of the immune response;
nanovaccines, also known as immunostimulatory SNAs, show up to (3) mimicking the desirable chemical and biological properties found in
80-fold increases in immunomodulatory activity potency, 700-fold nature; and (4) with unknown mechanisms [131].
higher antibody titers, and 400-fold higher cellular immune responses
to model antigens, as well as facilitate murine lymphoma treatment 4. Cancer vaccine types
[116]. Considering the above, SNAs can potently trigger the immune
system to create antibodies and cellular immunological responses [117]. “Vaccines can be categorized into types based on the technology that
SNAs can also alter immuneresponses. The injection of SNA-NPs into they use to initiate an immune response”. This technology is referred to

7
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

as a ‘vaccine platform’. Cancer vaccines are classified into cell-, peptide-, APCs and exposed on the cell surface in association with HLA molecules
viral-, and nucleic acid-based ones (Fig. 5). after administration. Tcells can recognize surface antigens that trigger
an immune response unique to malignancy. Compared with other vac­
cine types, peptide-based vaccines provide several benefits, particularly
4.1. Cell-based cancer vaccines
in terms of production simplicity and safety [137]. Examples of
peptide-based vaccines include the HBV and HPV vaccines for liver and
Typically, whole or fragmented cells are used to create cell-based
cervical malignancies [138].
cancer vaccines, which almost always contain tumor antigens and
trigger stronger immune responses. DC vaccines are a crucial subset of
cell-based vaccines. Customized neoantigen cancer vaccines based on 4.3. Virus-based cancer vaccines
DCs have shown promising antitumor effects in clinical trials. However,
DC vaccine development is constrained by laborious procedures and Numerous viruses have immunogenic properties, and their genetic
high costs. Tumor cell–based vaccination is a simple technique that uses makeup can be altered to include TA-encoding genes. Consequently,
allogeneic or autologous tumor cells obtained from patients to create viruses serve as the foundation for cancer vaccination. Adenoviruses,
cellular vaccines [132,133]. Tumor cell lines can be genetically altered poxviruses, and alphaviruses are the most commonly used vaccine
to increase the immune response against entire tumor cells by adding vectors [139,140]. Adenoviruses are recombinant viruses that can
genes encoding cytokines, chemokines, and costimulatory molecules or spread infections via immune cells. Vaccines made from modified vi­
suppressing immunosuppressive genes. The drawback of this method is ruses can expose the immune system to numerous tumor antigens and
the occasional difficultyof gathering a sufficient number of cells to thus achieve antitumor immunity. Vectors can also be created using
trigger an efficient immune response [134]. DCs are highly specialized oncolytic viruses. In addition to supplying tumor antigens, viruses can
APCs that activatenaive T cells and are used to create cell-based cancer lyse tumors, release tumor antigens, boost vaccine efficiency, and create
vaccines [135]. In DC-based vaccine production, DCs are supplied with a long-lasting immunological memory. However, viral vector–based
various tumor antigens in the form of DNA, RNA, tumor lysates, vaccine production procedures are complex, and most viral vectors are
tumor-derived proteins, or peptides. Various DC vaccines have been attenuated or exhibit replication defects. An important benefit of
developed based on DC subpopulations. DCs derived from monocytes virus-based vaccinations is that the immune system effectively reacts to
(Mo-DCs) and leukemia cells (DCleu) are the two primary types of DCs viruses, with innate and adaptive mechanisms collaborating to induce
used in DC vaccines. DC cancer vaccines have been investigated in phase potent and long-lasting immune responses [141]. However, repeated
I, II, and III clinical trials because a sufficient number of DCs can be vaccinations may not be as effective asan antiviral immune response,
cultured [136]. which may neutralize the vector. Oncolytic viral vaccines represent
novel promising strategies. Oncolytic viruses locate, capture, infect, and
destroy tumor cells while fostering antitumor responses. Oncolysis oc­
4.2. Peptide-based cancer vaccines
curs after the oncolytic viruses infect tumor cells to release reactive
oxygen species (ROS) and cytokines that activate immune cells
To elicit an appropriate immune response, peptide-based cancer
[142–144]. One such oncolytic virus vaccine is T-VEC, a first-generation
vaccines use highly immunogenic and tumor-specific peptide antigens.
recombinant product containing the herpes simplex virus [145].
Peptide-based subunit vaccines, such as synthetic and chemical versions
Adenovirus is another frequently used oncolytic virus because of its
of known or suspected individual tumor antigens, elicit potent immune
simplicity and wide range of host cell tropism [146].
responses to specific tumor antigen locations. An effective way to pre­
vent and cure viral infections is to administer peptide-based subunit
vaccinations along with adjuvants. Recent studies have demonstrated 4.4. Nucleic acid–based cancer vaccines
strong antitumor activity, particularly in subunit vaccines based on
VLPs, which elicit cellular immune responses. Personalized cancer Nucleic acid vaccines encoded by either DNA or RNA have great
vaccines are currently being developed using synthetic peptides and potential as cancer vaccine platforms because of their simplicity and
peptide vaccination techniques. Antigenic peptides are picked up by ability to generate potent MHC I-mediated CD8 + T-cell responses[147].

Fig. 5. Different types of cancer vaccines (created with Biorender.com).

8
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Multiple antigens can be simultaneously delivered using nucleic acid messenger RNAs (mRNAs), miRNAs, and siRNAs, have become an
vaccines to stimulate humoral and cellular protection. Furthermore, important class of medications for the treatment and prevention of a
full-length tumor antigens can be encoded via nucleic acid vaccines, wide range of illnesses, including cancer, genetic disorders, diabetes,
allowing APCs to crosspresent different epitopes or simultaneously inflammatory diseases, and neurodegenerative diseases [160–165].
present multiple antigens. Finally, nucleic acid vaccines arerapid and RNA-based treatments strongly affect immunotherapy. As opposed to
easy to create, thus holding promise for the development of customized conventional small-molecule medicines or proteins, RNA therapies can
neoantigen vaccines. Nucleic acid vaccines show advantages over con­ exertremarkable regulatory effects on the treatment of targeted cells by
ventional vaccines, including safety, specificity in generating immune either boosting the production of particular proteins or selectively
responses to target antigens, activation of both humoral and cellular knocking down specific genes to variable degrees. A further advantage
immunological responses, low production costs, and ease of manufac­ of RNA therapies is thatthey are more practical and simpler to construct
ture [148]. than protein-based medications.
Engineered DNAs encoding one or more TAs constitute DNA cancer The clinical implementation of RNA-based cancer therapy is
vaccines. DNA vaccines migrate from the cytoplasm to the nucleus after hampered by the instability of the RNAs and presence of various phys­
crossing the cell membrane of APCs to begin transcription. Conse­ iological obstacles preventing RNA distribution and transfection [166,
quently, the host machinery translates mRNAs into TAs in the cyto­ 167]. For instance, target protein expression can be altered by inhibitors
plasm, and the resulting antigens are administered to the APC to elicit an such as siRNA, miRNA, or positive regulatory RNAs [168]. Whereas
immunological response [149]. RNA vaccines have gained popularity naked RNAs have some limitations, such as poor chemical stability,
because of long-term expression and the subpar immunogenicity of DNA short half-life, and nuclease degradation, mRNA delivery aims to posi­
vaccines compared with those of other vaccination platforms [150]. tively and purposefully regulate protein expression. In addition, mRNA
Over the past 10 years, preclinical and clinical tests have been con­ drugs do not carry the risk of insertional mutations, have more consis­
ducted on several DNA cancer vaccines. Cervical cancer has been the tent and predictable protein expression kinetics, are simple to synthe­
subject of substantial research regarding DNA vaccination. Patients with size, and have a higher transfection efficiency [169–172]. The inherent
premalignant high-grade cervical intraepithelial neoplasia have defense systems of the human body, e.g., the different exonucleases and
demonstrated encouraging results with VGX3100, a DNA vaccine RNases responsible for RNA destruction in major organs or tissues and
against the HPV-16/HPV-18 E6 and E7 oncogenes [151]. Two phase III the innate immune system for RNA clearance, are also more likely to
clinical trials are currently underway to assess the safety and efficacy of clear external RNA [162,173].
this vaccine. A DNA vaccine against cervical cancer, GX-188E, combines NP-based delivery methods have been investigated as prospective
several epitopes and can target and activate DCs. A GX-188E phase II RNA delivery tools for both in vitro and in vivo applications to overcome
cervical cancer investigation provided encouraging results[152]. In a these immunogenic obstacles and ensure the safe distribution of RNA
recent preclinical investigation, a synthetic DNA multineoantigen molecules to their target areas [174,175]. NPs can be used to stabilize
vaccination was used to establish a therapeutic antitumor response by RNAs, e.g., protect them against enzymatic breakdown and immune
primarily activating CD8 + T-cell responses in mouse tumor models system clearance,and develop tailored delivery systems [176]. NP-based
[153]. Additionally, early clinical trials on the treatment of numerous platforms facilitate the delivery and penetration of RNA into infiltrated
prostate and breast malignancies using DNA cancer vaccines have immune cells at tumor sites [177,178]. The high potency, specificity,
demonstrated their safety and tolerability [154,155]. adaptability, rapid and large-scale development capabilities, possibility
Genetic materials encoding TAs are delivered as mRNAs through of low-cost production, and safety of mRNA vaccines make them
mRNA vaccination. The cytoplasm serves as the site of translation for attractive and effective immunotherapeutic platforms against cancer.
mRNA vaccines, which,therefore, do not need to enter the nucleus Recent developments in mRNA vaccine design and delivery have
[156]. mRNA vaccines have higher levels of immunogenicity than DNA accelerated the research and clinical use of mRNA cancer vaccines.
vaccines. The transient production of mRNA-encoded antigens allows Personalized antitumor immunotherapies using mRNA-based cancer
one to manage antigen exposure more effectively and lower the risk of vaccines have gained popularity. DCs must effectively deliver and
long-term exposure. However, RNA is broken down more easily than translate tumor antigens for antigen presentation to achieve strong
DNA, which is a drawback of RNA vaccines. Nevertheless, stability can antitumor efficacy. In addition, the vaccine may exertan adjuvant effect
be increased through several modifications. The clinical development of by inducing an innate immune response to boost the full activation of
mRNA vaccines has progressed slowly because ofproblems with stabil­ adaptive immunity [179]. For example, the COVID-19 mRNA nano­
ity, production of patient-specific vaccines, and delivery. Multiple vaccine produced by BioNTech and Moderna uses mRNA-encoded
mRNA vaccines have been successfully generated and released because coronavirus spike protein to trigger an immune response.
of the COVID-19 pandemic, demonstrating the platform’s excellent
adaptability, safety, and prospective immunogenicity[148]. The devel­ 5. Nanovaccine types
opment of mRNA cancer vaccines is currently in various stages. Patients
with stage III or IV melanoma well respond to TriMix, animmunosti­ 5.1. Neoantigens
mulant mRNA vaccine that encodes CD70 and CD40L and a constitu­
tively active version of TLR4 [157] while eliciting robust CD8 + T-cell Neoantigens are self-antigens produced by tumor cells as a result of
responses. Moderna developed mRNA-252, an additional immunosti­ genetic abnormalities, including somatic mutations [180]. Novel pro­
mulatory mRNA vaccine, to treat lymphoma, which is currently un­ teins or peptides derived from dysregulated RNA can also serve as
dergoing clinical study under the designation NCT03739931 and neoantigen sources. Neoantigen vaccines composed of DNA, mRNA, or
encodes human OX40L, IL-23, and IL-36. The BNT111 mRNA vaccine, artificial peptides hold promise for cancer treatment [181]. Tumor
which encodes four TAAs (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE), neoantigens present a novel method of tumor immunotherapy based on
has been successfully used to treat melanoma [158]. The clinical testing antigens produced by tumor viruses with genome-integrated tumors and
of customized mRNA vaccines from BioNTech and Moderna revealed mutant proteins exclusively expressed in tumor cells. These neoantigens
positive antitumor outcomes. The Moderna vaccine mRNA-4157 have immunogenic properties, are tumor-heterogeneous [182], and can
(encoding up to 34 neoantigens) and BioNTech vaccine BNT122 be produced by virally encoded open reading frames in tumors with a
(encoding up to 20 neoantigens, NCT04486378) are two personalized viral infection, such as HPV-positive cervical cancer and EBV-associated
mRNA cancer vaccines currently undergoing phase II clinical studies nasopharyngeal carcinoma [183–185]. Neoantigens can be identified by
[159]. sequencing the genomes of both cancerous and healthy cells or using
In the last two decades, RNA-based therapeutics, including MS-based proteomics.

9
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

The low immunogenicity of neoantigens is one of their main prob­ cancer vaccines, which have demonstrated considerable therapeutic
lems. Nanovaccines can, to some extent, enhance the delivery and, effectiveness in mouse tumor models, having the capacity to enhance
thereby, the immunogenicity of neoantigens. Synthetic high-density li­ cytosolic CDN distribution and stimulate immunological responses. The
poprotein nanodiscs can be used as clinically secure and scalable STING-activating PC7A nanovaccineboosted antigen-specific
nanomaterials to facilitate the delivery of peptide neoantigens through CD8 + cytotoxic T-cell infiltration in the TME when intratumorally
disulfide conjugation, while cholesterol-modified adjuvant therapy for administered to mice with melanoma. The accumulation of the
draining lymph nodes can treat cancer by inducing antigen-specific STING-activating PC7A nanovaccine in tumors also increases the pro­
CD8 + T-cell responses [186]. The treatment of melanoma-bearing duction of CXCL9 in myeloid cells and thus improves the recruitment of
mouse models with a neoantigen nanovaccine resulted in a median IFN-expressing CD8 + T cells from the periphery into the TME [205].
survival time of ~8 d (cf. XX d in the control group) and mean recur­ The attachment ofCDNs to STING was shown to inducestructural
rence time of 16 d (cf. 11 d in the control group). Additionally, the changes activating the STING signaling pathway [206]. After vaccina­
prevalence of neoantigen-specific T lymphocytes increased 10-fold after tion, both CD8 + and CD4 + T-cell responses substantially exceeded
free vaccinations, raising levels of TNF-α and IFN-γ. The anticancer ac­ those elicited by free CDNs. More recently, CDNs have been incorpo­
tivity in spleen cells was noticeably more potent in the nanovaccine rated into NPs consisting of endosomolytic polymersomes assembled
group than in the other study groups [187]. MHCs can cause neo­ from pH-responsive diblock copolymers for the enhanced cytosolic de­
antigens to be exposed on the cell surface, where they are recognized by livery of CDNs [207]. Luo et al. [208] developed a STING-activated
T lymphocytes [188,189]. The two types of tumor antigens are TSAs and pH-responsive polymer nanovaccine, presumably by disrupting subcel­
TAAs[190]. TAAs appear to be overexpressed in tumor cells but are lular organelles and exposing nucleic acids in the cytosol. These results
rarely expressed in normal cells because they areencoded by unmutated demonstrate that STING agonist–based nanovaccines can improve the
genes [191]. Given that TAAs are typically host proteins, both the cen­ bioavailability and therapeutic efficacy of CDNs, enhance STING
tral and peripheral tolerance mechanisms are applicable to them [192, signaling, and potentiate immune responses tocancer immunotherapy.
193]. Neoantigens are excellent targets for T-cell cancer immunotherapy Type I IFN signaling is heavily reliant on immunotherapy [209]. The
and cancer vaccines. Synthetic neoantigen medications can be created heterodimeric interferon alpha receptor, which initiates downstream
according to the condition of the tumor cell mutation using the immune signaling cascades such as JAK-STAT and promotes the transcription of
activity of neoantigens to achieve the desired therapeutic effect. Neo­ IFN-stimulated genes, mediates the downstream effects of type I IFNs
antigens can be divided into shared and personalizedones [31,194]. [210]. Type I IFNs have several effects on immune cells, including the
Shared neoantigens are mutant antigens present in different cancer pa­ enhancement of cytotoxic capacity and IFNsecretion potential of natural
tients but not in healthy DNA. For patients harboring the same mutant killer cells and the promotion of antigen-presenting cell differentiation,
gene, shared neoantigens with high immunogenicity can be tested for maturation, and migration [211]. Type I IFN signaling is essential for
use in broad-spectrum therapeutic cancer vaccines [195,196]. Person­ innate immune responses, as shown by reduced T-cell priming and
alized neoantigens are mutant antigens that are distinct from most impaired antigen presentation in IFN-R-knockout CD8 + DCs [212] and
neoantigens and differ entirely from patient to patient. Therefore, increased metastatic spread of tumor cells in IFN-R-knockout mice
personalized neoantigen–based medicines can only be applied to indi­ [213]. Type I IFNs exert an antitumor effect by reducing tumor growth
vidual patients as a part ofpersonalized therapy [197]. and boosting the production of class I MHCs, which arenecessary for
tumor recognition by CD8 + T lymphocytes. Mounting evidence sug­
5.2. STING agonist–based nanovaccines gests that type I IFNs also reduce VEGF production, which inhibits tumor
angiogenesis [214].
Despite their revolutionary effect on cancer treatment, immuno­ Owing to abnormalities in the expression or activity of DNA repair
therapies fail to elicit responses in a considerable proportion of patients. proteins, tumors exhibit genetic instability [215], which causes high
Targets that trigger or strengthen antitumor immune responses have intrinsic amounts of cytoplasmic DNA and constitutive cGAS/STING
been the focus of recent studies. One such novel target is STING, also activation during carcinogenesis [216–218]. The intrinsic activation of
known as the stimulator of interferon (IFN) genes, an endoplasmic STING in tumor cells has led to the evolution of abnormalities in the
protein that promotes the synthesis of proinflammatory cytokines such STING signaling pathway, which has been used by numerous malig­
as type I IFNs [198]. STING is a signaling protein linked to the endo­ nancies to circumvent immune surveillance mechanisms [218,219].
plasmic reticulum that regulates the transcription of multiple immune With improved T-cell adhesion to the endothelium and facilitated
system–related genes and strongly contributes to innate immune re­ recruitment of tumor-infiltrating lymphocytes, STING activation in host
sponses to bacteria and viruses [199]. When cytolytic DNA is detected stromal cells, especially endothelial cells, increases vascular perfusion
by cytosolic cyclic GMP-AMP synthase (cGAS), STING promotes the and the expression of E-selectin, VCAM-1, and ICAM-1. In patients with
release of type I IFNs and proinflammatory cytokines to initiate in­ colon and breast cancer, increased T-cell infiltration and prolonged life
flammatory pathways and eliminate pathogens [199]. Additionally, have been closely linked to endothelial STING expression in tumors
STING-dependent signaling can be used to induce adaptive immunity [220]. High STING agonist concentrations induce apoptosis and
after DNA vaccine injection [200]. CD8 + DCs cangenerate type I IFN vascular necrosis. A mouse tumor model demonstrated that high-dose
through the STING pathway to induce antigen cross-presentation and DMXAA-based treatments reduced tumor development or encouraged
the priming of CD8 + T cells [201]. Additionally, tumor-derived STIN­ regression based on vascular necrosis and tumor starvation/hemor­
G-activating components can be recognized by B cells and other rhagic necrosis [221]. High local concentrations of STING agonists may
CD11b+ tumor-infiltrating host APCs, which leads to the release of accelerate T-cell death. High-dose DMXAA regimens fail to yield greater
STING-mediated type I IFNs produced by leukocytes and the priming of therapeutic advantages, even when paired with other immunotherapies,
cytotoxic NK cells for tumor cell eradication [202]. such as tumor antigen-specific CD8 + T-cell transfer, because of their
The STING pathway also participates in radiotherapy-induced or negative impact on the recruitment and function of immune cells within
naturally occurring stimulation of antitumor T-cell responses [203]. the TME [222]. Recent studies have suggested that when injected
According to previous studies, cyclic dinucleotides (CDNs) can be more intratumorally into mice with established breast cancer, lung carci­
effectively delivered to the cytosol by NPs, which can trigger immuno­ noma, or melanoma, low doses of cGAMP and ADU-S100 (STING ago­
logical reactions. For instance, a cancer nanovaccine produced by nists) enhance the local production of antiangiogenic factors that aid
encapsulating cyclic di-GMP into PEGylated lipid NPs may activate vascular normalization [220,223]. According to earlier research, the
CD4 + and CD8 + T-cell responses more than CDNs alone [204]. CDNs therapeutic success of such interventions relies on the infiltration of
have also been investigated as the potential components ofintralesional tumors by CD8 + Tcells, which is predominantly induced by STING

10
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

activation in tumor vascular endothelial cells and type I IFNs generated vaccinations. Additionally, the main antigens that cause mutations in
by these cells [220,223,224]. tumors can vary between patients and even cancers. As a result, the
majority of patients with tumors have few common antigens elsewhere
5.3. Artificial APCs (aAPCs) in the body, while the tumor cells themselves contain perfect and
complete antigens that trigger tumor-specific immune responses
APCs serve as a bridge between innate and adaptive immune re­ [244–246]. Therefore, tumor cells are the best source of antigens for
sponses. When an antigen is internalized, APCs can exhibit antigen class creating tumor vaccines [132,247,248]. Tumor cell–derived nano­
I and II MHCs on the membrane, together with costimulatory signals, to vaccines are classified based on their cellular components, including
activate antigen-specific T cells, which are essential for the adaptive tumor whole-cell fractions, extracellular vesicles, and cell membrane–­
immune response [225]. APCs, such as DCs, can transmit information coated NPs.
from vaccines to T or B cells, DCs, and macrophages, which are Nanovaccines made from tumor cells are created by directly injecting
responsible for antigen capture, processing, and presentation via intact tumor cells into nanovesicles. The nanovaccines not only preserve
MHC-II. MHC-II subsequently stimulates these cells to produce adaptive all tumor cell antigens, but can also cross cell or tissue barriers and have
immune responses that are essential for cancer immunotherapy [226, prolonged circulation durations [249]. The nanovesicles utilized in this
227]. Given the importance of DCs in cancer immunotherapy, autolo­ study were comparable to exosomes in terms of size, surface-labeled
gous DC-based cancer vaccines have received substantial research in­ proteins, and morphology but yielded 100 times more thanconven­
terest. These vaccines can beprepared by isolating patient-derived DCs tional vaccines [250]. Nanovesicles are smaller than complete tumor
and activating them with cancer antigens to produce antigen-specific cells, therefore having the ability to overcome biological barriers and
DCs. The resulting specifically targeted DC vaccines can be adminis­ circulate longer. Nanovesicles also preserve the TAAs and cytoplasmic
tered to relevant patients to stimulate immune responses for cancer components of tumor cells. In particular, APCs favor the phagocytosis of
therapy [228]. However, the time- and cost-ineffectiveness of this NPs. As a result, nanovaccines are more likely to be phagocytosed by
strategy severely restrict its use in clinical settings. APCs, increasing lymph node retention and triggering
To overcome these barriers, aAPCs have been designed as T-cell lymphocyte-mediated antitumor immune responses [251]. Genetic en­
activation and proliferation platforms replicating the interactions be­ gineering endows tumor cell–derived nanovesicles with the ability to
tween DCs and T cells [225,229–233]. aAPCs comprise a variety of carry specific molecules. For instance, CAFs, which are the most prev­
systems that use biomaterials or modified cells and are increasingly used alent stromal cells in TMEs, promote the proliferation and invasion of
in immunological and clinical applications because of their ready tumor cells and have been chosen as targets for tumor immunotherapy.
availability[234,235]. Synthetic aAPCs based on biomaterials have been To create nanovesicular vaccinations, tumor cells can be genetically
successfully used for the in vitro and in vivo production of antitumor modified to express FAP [252]. These vaccinations contain both tumor
immune responses [236]. A cognate antigenic peptide given in the self-specific and FAP antigens, thereby targeting both tumor paren­
context of MHC and costimulatory molecules, which can bind to TCRs chymal and mesenchymal cells and producing notable anticancer effects
and costimulatory receptors to activate T cells, are the two components in tumor-bearing mouse models. Nanoengineering is a more practical
of aAPCs [237]. According to Eggermont et al. [231], aAPCs are syn­ and financially feasible approach than exosome isolation. Large-scale
thetic APCs with a predetermined composition and regulated and uni­ applications and clinical translation depend on reliable production
form signal representation. Genetically altered cellular aAPCs, such as processes and simple access to the necessary technologies.
K562 human leukemic cells [238] and NIH/3T3 murine fibroblasts, have
been used to activate cytotoxic CD8 + T cells [239]. Another strategy 6.2. Whole tumor cell vaccines
involves the use of bioengineering techniques to create synthetic aAPCs
[240,241]. The physicochemical properties of aAPCs, such as their size Owing to the wide range of antigens found in tumor cells, whole
and shape, may affect T-cell activation; hence, aAPCs can be created by tumor cell vaccines have drawn much interest [132]. A higher rate of
adjusting these properties for optimal immunomodulation and thera­ tumor escape reduction is possible with whole-cell immunization than
peutic efficiency. with single-epitope vaccines [253]. Depending on the location of the
tumor cells, these vaccines can be divided into allogeneic and autolo­
6. Cancer cell–based vaccines gous ones [254]. Personalized therapy is made possible by autologous
vaccinations, which employ the patient’s own tumor cells as the antigen
6.1. Tumor cell–derived vaccines source [255]. Tumor cell lines generated from individuals of the same
race are used in allogeneic vaccinations, offering the advantages of mass
Tumor immunotherapy involves stimulating the immune system to production and simple standard quality control. However, the immune
create an antitumor immune response and thus effectively prevent system does not respond strongly to unaltered tumor cells [256]. GVAX
tumor emergence, growth, and recurrence [242]. Tumor cell–derived Pancreas, a genetically engineered vaccine, utilizes tumor cells that have
vaccines can effectively deliver TSAs to APCs and activate been manipulated to express GM-CSF, which is used as an immune
tumor-specific T cells. Tumor vaccines are generally classified as pre­ adjuvant and boosts DC survival and antigen-presenting ability
ventive or therapeutic [186]. Therapeutic tumor vaccines are used to [257–259]. In addition to suppressing regulatory T-cell (Treg) activity,
deliver antigens specific to tumor cells and stimulate the immune system GVAX Pancreas generates specific T-cell immunity against tumor anti­
to create specific immune cells or antibodies and kill tumor cells. Pro­ gens and mesothelin. Clinical trials have shown that the combination of
venge®, a tumor vaccine, is used to treat metastatic hormone-resistant GVAX Pancreas with CRS-207 increases the survival time in patients
prostate cancer with no or mild symptoms. The U.S. Food and Drug with metastatic pancreatic cancer [260]. Autologous tumor whole-cell
Administration (FDA) authorized the first tumor vaccine for marketing vaccination with high FAP expression has beendeveloped using the
purposes in 2010. vaccination-targetedtumor cells and CAFs, resulting in a considerable
APCs, particularly DCs, are required to absorb a variety of TSAs for drop in CAFs, removal of the immunosuppressive TME, and increased
optimal T-cell activation when using tumor vaccines to trigger tumor recruitment of effector T cells to enhance antitumor effectiveness.
immune responses [34,243]. Thus, the development of tumor vaccines Enriching the antigen spectrum increases not only the production of
would benefit from the use of a greater variety of tumor antigens and immunostimulators but also the immunogenicity of tumor vaccines
improved delivery techniques, and these vaccines should be designed to [261]. The administration of vaccines to animals with tumors boosts the
maximize tumor immunogenicity. Given the variability and complexity production of immunoregulatory cytokines, resulting in a high profile of
of tumor antigens, few of them can be exploited to create universal anticancer cytokines. This behavior implies that an autologous whole

11
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

tumor cell vaccine can be modified to create a semiallogeneic whole antigens and GM-CSF, preserving the recruitment and activation of DCs
tumor cell vaccine capable ofefficiently using the allogeneic response to while eliciting a potent T-cell response. In the spleen and tumors of
boost the anticancer immune effect. Tumor vaccines have also been used immunized mice, the fraction of activated effector CD8 + T cells was
to boost immunogenicity by downregulating gene expression. By higher, but the Treg number was lower. Therefore, injectable hydrogels
altering MYC oncogenes, one can change the ability of the immune offer a special way of targeting the immunosuppressive TMEs and
system to recognize cancer cells [262]. To generate an acceptable dose exhibit the advantages of easy synthesis, high drug-loading capacity,
of whole-cell vaccination, tumor cells from patients may not be suffi­ controlled release, and minimal toxicity [272]. Peptide hydrogel–based
cient; hence, in vitro tumor cell growth is necessary. Despite providing a TCL delivery systems are a promising therapeutic option for several
large spectrum of personalized tumor antigens and CD4 + and malignancies. TCLs have been exploited as rich sources of antigens to
CD8 + T-cell epitopes, whole tumor cell vaccines face a number of stimulate the immune system against cancer cells. TCL vaccines effec­
challenges. Genetic engineering can increase the release of immune tively provide a variety of antigens to elicit T-cell responses and produce
factors, improve the immunogenicity of tumors, and create carriers for DCs with immunomodulatory cytokines to promote tolerogenic trans­
the transport of chemotherapeutics, NPs, and antibodies. formation. Soluble TCLs with antigens and cytokines are intrinsically
unstable and therefore frequently suffer frompoor DC uptake, ineffective
6.3. Tumor cell lysate–based vaccines antigen cross-presentation, and insufficient CTL response activation
[273]. Therefore, the development of suitable delivery vectors is
The formation of homologous tumor lysates enables the production necessary to overcome these limitations and improve the efficiency of
of a wide range of TAAs that can potentially enhance antitumor im­ antigen presentation.
munity. In cancer immunotherapy, vaccines based on tumor lysate an­
tigens appear to be more clinically beneficial than peptide-based ones 6.4. Wholetumor RNA vaccines
[263,264]. Furthermore, the simultaneous use of MHC class I- and class
II-restricted antigens from tumor cell lysates is expected to result in Generally, tumor mRNA vaccines are safer than DNA and live
stronger antitumor responses and longer-lasting T-cell memories[265]. attenuated vaccines and can transcribe whole tumor cell antigen com­
APCs do not effectively absorb these lysates because of their low ponents to cause the extensive activation of specific tumor immune re­
immunogenicity and small number of TSAs, and TCLs rapidly degrade sponses. Whole tumor RNA vaccines have several advantages over
within the body [266]. Therefore, engineering efforts have focused conventional tumor vaccines, including the ability of the tumor mRNA
primarily on altering the immunogenicity of TCLs. To increase immu­ to simultaneously encode multiple tumor antigens;moreover, mRNA can
nogenicity, tumor cells have been genetically modified to control the bypass the MHC classification restrictions and obtain immunogenicity
key components of the tumor immune response. For instance, blocking without an adjuvant and no insertional mutations, and does not inte­
the STAT3 signaling system in hepatocellular carcinoma (HCC) cells grate into the host genome [274–276], Conversely, RNA vaccines are
prevents tumor cell growth and promotes cell death [267]. TCL@poly­ inherently unstable. RNases outside the cell rapidlydestroy naked RNA,
dopamine (PDA)NPs promote surface molecule expression and cytokine rendering it inactive before it can be localized to APCs. Additionally, the
release, facilitating antigen absorption by DCs and inhibiting tumor negative charge of naked RNA may hinder its entry into APCs [277]. To
formation. Both water-soluble and -insoluble antigens have been enable the effective distribution of RNA, more effective drug delivery
detected in whole-cell lysis fractions. Tumor vaccination can transmit a methods are required. Numerous negatively charged phosphates present
wider array of tumor antigens to the body if a water-insoluble compo­ in nucleic acids such as RNA enable the electrostatic binding of cationic
nent is included. An increased antigen load in tumor vaccines results in a substances. Lipid vesicles, known as cationic liposomes, are examples of
broader immune response targeted specifically against cancer cells, cationic lipid NPs (LNPs)that are frequently used for the delivery of
making the vaccine more potent. Consequently, polymeric NPs can be nucleic acids and small-molecule medicines. Cationic liposomes, which
used to increase the loading of tumor antigens. Nanovaccines were contain ionizing lipids, are the first-generation RNA delivery carriers
shown to cure 25% of mice with melanoma and triple-negative breast that have been studied in (pre)clinical trials. At all physiological pH
cancer [268]. The cure rate of nanovaccines in melanoma-bearing mice levels, these lipids maintain a positive charge and easily condense into
increased by 40% when these vaccines were combined with the immune anionic RNA. One of the most popular cationic lipids that effectively
checkpoint inhibitor PD-1 antibody. In another study, hypochlorite encapsulates RNA is DOTAP[278]. The efficient induction of systemic
treatment improved the immunogenicity of TCLs. When PLGA NPs immune activation by cationic liposomes containing
containing tumor lysates that have undergone hypochlorite oxidation DOTAP-encapsulated mRNA increased the expression of MHC I/II B7
wereuptaken by DCs, they effectively induced DC maturation (Fig. 1). costimulatory molecules and maturation markers in splenic APCs [279].
Animals receiving the PLGA NP formulation lived longer than those Total RNA isolated from liver cancer cells was used to create a
receiving free oxidized tumor lysate vaccination [269]. According to Shi DC-targeted RNA LNP tumor vaccine that increased RNA stability and
et al. [270] and Carroll et al. [271], TCLs with chitosan NPs transfection efficiency, encouraged DC phagocytosis, and boosted anti­
surface-modified with mannose as a carrier (Man-CTS NPs) improved tumor immunity, thus inducing specific antitumor immune responses
the absorption of NP-associated antigens. Adjuvants and a multiarm [280]. Whole-cell tumor RNA antigens offer a broad-spectrum approach
poly(ethylene glycol) (8-armPEG)/oxidized dextran dynamically cross­ compared to specific tumor RNA antigens, negating the need to discover
linked hydrogel were used to recover tumor cell lysates from surgically particular TAAs or neoantigens. Immune checkpoint inhibitors may be
removed tumors and use themas antigens. These findings demonstrate necessary in conjunction with whole tumor RNA vaccinations to provide
that the subcutaneous injection of hydrogels can recruit DCs into the in synergistic antitumor effectiveness because PD-L1 is expressed as a
situ stroma and cause potent tumor-specific immune responses. A result of whole tumor RNA vaccines. The entire tumor RNA can also be
customized approach for cancer prevention and treatment in post­ effectively transported using a number of new RNA carriers, including
operative patients has been enabled by the successful inhibition of the polymers and pH-responsive ionizable lipids.
postoperative growth of residual tumors in numerous animal models.
According to an in vivo study by Song et al. [272], TCLs loaded with 6.5. EV-based cancer vaccines
self-assembled peptide hydrogels produced potent T-cell responses.
Injectable and self-assembled poly(L-valine) hydrogels were used as EVs, also known as tumor-derived extracellular vesicles (TEVs), are
delivery systems for antigens and immune boosters affecting DC mod­ secreted by tumor cells and are important for intercellular communi­
ulation [272]. APEG-b-poly(L-alanine) hydrogel loaded with dual cation. Owing to the presence of immunogenic components such as
checkpoint inhibitors demonstrated a continuous release of tumor nucleic acids, TAAs, and damage-associated molecular patterns that

12
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

might trigger the maturation of immune cells to initiate an anticancer long-term immunological memory protection while enhancing anti­
response, TEVs are promising tumor vaccines [281]. EVs are frequently tumor effectiveness. In addition to delivering small-molecule drugs,
used to treat several diseases, including cancer, as a new type of cell-free TEXs can be customized to load AuNPs. For instance, tumor cells can be
therapy [282]. Exosomes and microvesicles have been the main focus of grown in a medium containing HAuCl4, and the resulting AuNPs can be
recent studies on the use of TEVs as vaccines. directly released as TEX-encapsulated AuNPs (Au@MC38) after syn­
Exosomes produced by tumor cells have sizes of 30–150 nm and thesis by the cells [300]. Reactive oxygen species (ROS) are generated
feature a lipid bilayer structure containing numerous proteins. Tumor- when radiation-induced DNA damage is amplified by Au@MC38, which
derived exosomes (TEXs) from several cancers transport a variety of preserves the biological integrity of the original cancer cells. As a result,
functional molecular cargoes from the cell membranes and nuclear the ICD of tumor cells increases, boosting the immune response. Given
endosomes of primary tumor cells, which can be transmitted to recipient that T-cell activation depends on the MHC presentation of antigenic
cells [86,283,284]. The shape of their lipid membrane allows exosomes peptides, the loading of TEXs into DCs can also improve the capacity of
to carry various chemicals for improved antigen delivery, immunosup­ TEXs to elicit immunological responses. Additionally, TEX-loaded DCs
pressive inhibition, and extended circulation times. Owing to the nature can help process tumor antigens produced from TEXs and display the
of their lipid bilayers, TEXs are also attractive delivery vehicles for processed tumor antigenic peptides in MHC slots [301].
hydrophilic/hydrophobic pharmaceuticals or even NPs [285,286].
Numerous proteins on the exosomal membrane have effective cellular 6.6. Tumor-derived microvesicle vaccines
absorption and tailored homing properties, thus enabling the delivery of
internal payloads to the tumor location and immune response stimula­ Tumor-derived microvesicles (TMVs) are EVs with diameters of
tion [287]. After absorption by DCs, antigens from donor tumor cells 100–1000 nm that are released by tumor (or other) cells in the TME and
present in TEXs are exposed to MHCs, prompting naive T cells to pro­ contain various bioactive molecules, including proteins, nucleic acids,
duce antitumor responses. TEXs contain higher concentrations of and other compounds that are linked to tumors and shed from the
immunostimulatory elements than cells [288,289] and are therefore plasma membrane. These biomolecules affect the properties and func­
more likely to trigger anticancer immune responses. Moreover, TEXs can tions of tumors, including metastasis, invasion, angiogenesis, and im­
evade immune system attacks owing to their transmembrane CD47. mune response [302–304]. As therapeutic tumor vaccines, TMVs are
Additionally, according to Huang et al.[290] and Zhang et al.[280], the produced by C6 glioma cells after exposure to ionizing radiation. This
number of TEXs released by cancer cells is typically 10 times greater vaccine, when exposed to radiation, releasestumor antigens that help T
than that of TEXs released by exosomes derived from healthy cells. cells infiltrate immunized rat tumors and facilitate tumor cell death,
Target molecule enrichment and immunostimulatory impact enhance­ drastically lowering the tumor volume [305]. TMVs have been shown to
ment can be achieved by the direct genetic manipulation of tumor cells carry innate DNA signals as well as the tumor antigen profile, which
that secrete TEXs, which is a realistic alternative for enhancing immu­ activate type I IFNγ through the cGAS/STING pathway and thus promote
nogenicity. Class II MHCs increased in TEXs produced by this species DC maturation, T-cell activation, and tumor rejection [306,307](Fig. 1).
when melanoma B16F10 cells were transduced with the MHC II trans­ TMVs can be taken up by DCs and enter lysosomes, increasing the pH
activator protein class II transactivator (CIITA) gene [291]. The mRNA and facilitating the processing and presentation of tumor anti­
levels of the inflammatory cytokines TNF and chemokine receptor 7 rose gen–bearing TMVs. TMVs can also trigger the release of calcium ions in
together with the expression of MHC class II and CD86 on the surface of lysosomes, encourage the nucleus to dephosphorylate the transcription
DCs following exosome vaccination. Therefore, CIITA-TEXs achieved factor EB, control the expression of CD80 and CD86, and promote DC
dramatically improved immunological responses. CT26-CIITA-derived activation and maturation. These studies show that effective TMVs can
TEXs increased Th1 immune responses, as evidenced by the increased be used as tumor vaccines [308]. The oral administration of a TMV
expression of TNF-α, IFN-γ, and interleukin (IL)− 12 and decreased vaccine to mice resulted in the absorption of ileal epithelial cells (IECs).
expression of IL-10 [292]. Human DCs loaded with melanoma TEXs TMVs activated the ileal epithelium via NOD2 signaling, prompting IECs
induce the in vitro production of IFN-γ from CTL clones and increase the to produce chemokines that attract CD103 + CD11c+ DCs. IECs deliv­
immune response against cancer [293]. As evidenced by their higher ered the TMV vaccine to the basolateral side, where DCs successfully
expression of IFN and lower expression of inhibitory IL-10 and TGF in collected and crosspresented TMV-derived antigens to activate CD8 + T
HCC animal models, TEX-DC-stimulated Tcells have a greater capacity cells. Tregs allow tumor cells to evade the immune system in malignant
for cytotoxicity than tumor lysate DCs and are more successful in elic­ tumors, making the patient’s immune system much less efficient in
iting immunological responses [294,295]. Huang et al.[296] engineered battling tumors[309,310]. A combination of oral tumor vaccines con­
HELA-Exos with a combination of TLR3 agonists and ICD inducers. HeLa taining TMVs extracted from mouse prostate cancer cells with cyclo­
Exos activated DCs in situ and specifically induced ICD in breast cancer phosphamide and GM-CSF considerably reduced Treg numbers via
cells. To enhance targeting and immunogenicity,LA, a breast-specific immune regulation, intercellular communication, inflammatory re­
immunodominant protein, was overexpressed in triple-negative breast sponses, and immune cell activation [311].
cancers [297]. Exosomes were released by MC38 tumor cells genetically
altered to overexpress IL-12 and TGF-1 shRNA. These exosomes 6.7. Tumor cell membrane–derived vaccines
improved the anticancer effects of DC-based immunotherapy and
deceleratedtumor growth [298]. Similarly, tumor xenografts or cells The ability of tumor cell membrane–derived vaccines to cultivate
expressing highlevels of EGFR were successfully transfected with the tumor cell membranes on a large scale, abundance of tumor antigens,
gene using the GE11 peptide. Let-7a, a tumor-suppressingmiRNA, was and ease of modification make them promising tumor treatment options.
delivered to cancer tissues expressing EGFR using genetically modified One potential technique for the creation of CCM systems is the devel­
GE11-positive exosomal vaccines, which dramatically reduced tumor opment of more individualized and innovative therapeutic approaches
growth by HMGA2 or RAS family members [299]. After the adminis­ using primary tumor cell membranes. Malignant tumors were treated
tration of modified TEXs to mice, the immune system produced more with human malignant melanoma cell-soluble membrane antigens
IFNγ and IL-2 from T cells, improved CTL responses in vivo, and boosted [312]. Unlike cellular vaccines, tumor cell membrane vesicles do not
CD4 + T cell and NK cell antitumor activity. Effects stronger than those include genetic material and offer the benefits of higher biosafety,
of untreated TEXs or combinations of TEXs and SEA were observed after simpler mass production, a longer storage period, and effective tumor
treatment with SEA-TEX, which suppressed tumor growth and increased targeting owing to the homology of the outer membrane. To increase the
longevity. Therapeutics are transported by TEXs around the tumor to efficacy and targeting precision of tumor vaccines, a tumor vaccine
synergistically reduce tumor growth, stop distant metastases, and offer (CMV-CpG/Apt) was generated from tumor cells by inserting

13
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

cholesterol-modified CpG and cholesterol-modified DC-SIGN aptamers surface to prevent ICNP aggregation and nonspecific phagocytosis.
as adjuvants into tumor cell membrane vesicles. With better delivery ICNPs demonstrated homologous and precise targeting with substantial
efficiency and more potent antitumor immune responses, CMV-CpG/Apt tumor penetration. Laser treatment with a single dose of ICNPs achieved
precisely targeted DCs for rapid accumulation in lymph nodes and complete tumor ablation, thus demonstrating promising synergistic
generated long-lasting immunological memory while successfully pre­ anticancer effects in vivo.
venting tumor growth [313]. Vaccines can be produced by anchoring
two immunostimulatory molecules (B7–1 and IL-12) to GPI, which in­ 6.9. Hybrid membrane–coated NP vaccines
duces potent antitumor protective immunity in tumor cells. When such a
vaccine is administered to mice bearing head and neck squamous cell Although tumor cell membrane–coated NPs hold promise for tumor
carcinoma tumors, tumor growth is inhibited, and the survival rate in­ therapy, they have limitations, such as poor immunogenicity and limited
creases [314,315]. Similarly, the embedding of MPL A as a lipid adju­ circulation. In contrast to monotypic cell membranes, hybrid cell
vant into lipid membranes induces DC maturation by targeting Toll-like membrane NPs can acquire additional properties from other cell mem­
receptor 4 [316]. Immunomodulatory lipocomplexes functionalized branes while retaining the salient characteristics of tumor cell mem­
with photosensitizer-embedded CCMs are known to inhibit tumor branes, such as their ability to target tumors and stimulate the immune
growth and metastasis [317]. system. Hybrid membranes can be created by fusing two cells together
or employing two cell membranes isolated from different cells [328].
6.8. Tumor cell membrane–coated NP vaccines Owing to their innate biocompatibility and capacity for prolonged cir­
culation, erythrocyte membranes were the first materials to be
Owing to the advancements in nanoscience and nanotechnology, NPs employed for biomimetic NPs [329]. When tumor cells and erythrocyte
have been extensively used in drug delivery. NPs are easily absorbed and membranes combine, immune cells in the spleen are exposed to tumor
cleared by the reticuloendothelial system and are therefore highly sus­ antigens, triggering an immunological response. The erythrocyte tumor
ceptible to ingestion and interactions with the body. Consequently, cell membrane–coated nanosilver vaccine could well target splenic APCs
membrane-coated NPs are employed in nanovaccines that utilize a va­ to activate different immune cells in the spleen and generate a more
riety of cell membranes, such as those from tumors, erythrocytes, potent T-cell immune response. In B16F10-Luc murine melanoma and
platelets, macrophages, bacteria, and neutrophils [251,318]. The ability 4T1-Luc murine mammary carcinoma models, this vaccine reduced
of tumor cells to self-home, escape from the immune system, and acti­ tumor metastasis [330]. Membranes coated with hollow copper sulfide
vate the same is essentially controlled by the membrane proteins on NPs (DCuS@NPs) displayed homogenous targeting and a considerably
their surfaces [319]. Therefore, tumor cell membrane encapsulation, longer circulation lifespan [331].
which provides NPs with a long circulation capability and delivers them
to self-targeting homologous tumors, can be used to duplicate these 7. Mechanism of action of nanovaccines
surface antigen structures from cells to NPs [103]. Thus, the creation of
tumor vaccines can be facilitated by increasing the number of design NPs play an important role in the delivery of antigens to tumor sites.
options and possible applications of NPs coated with tumor cell Antigens delivered by NPs are internalized via several endocytic path­
membranes. ways. However, the delivery, internalization, and presentation of anti­
Inorganic NPs coated with tumor cell membranes are potentially gens to APCs depend on various factors, including the size, surface
effective for cancer treatment because they induce localized inflamma­ charge, surface functionalization, and type of NPs. For instance, cationic
tion, thus encouraging the attraction of APCs and stimulating cellular NPs are internalized by APCs faster than other ones and often increase
absorption [13]. Liquid AuNPs with tumor cell membrane coatings have intracellular trafficking via endosomal escape [23,332]. In addition to
been developed as tumor-preventive vaccines[320]. Inorganic NPs improving antigen delivery to DCs, cationic dendrimer NPs with
enclosed in cell membranes can serve as carriers for the deliveryof adsorbed antigens activate DCs, causing the release of cytokines,
therapeutics or adjuvants. Porous silicon (PSi) plays an important role in including IL-1β and IL-12 [333]. DCs play an essential role in the co­
drug delivery becauseof its porous structure, biodegradability, and ordination of innate and adaptive immune systems (Fig. 5). As the ma­
compatibility. Additionally, PSi microparticles can enhance IFNγ pro­ jority of vaccines currently employed in clinical practice are exogenous
duction and antigen crosspresentation to exert anticancer effects [89, to cells, DCs are essential for vaccine-activated cellular immune re­
295,321–323]. sponses against viral and malignant illnesses. Hence, DC targeting using
To create a novel nanovesicular vaccine, Huang et al. [324] com­ nanovaccines has been the subject of numerous methodologies [334].
bined Psi NPs, gold, and tumor cell membranes to create CCM@ According to Gazi and Martinez-Pomares [23], CD4 + and
(PSiNPs@Au), which demonstrated superior immunostimulatory and CD8 + T-cell responses are stimulated by the expression of cell-surface
photothermal effects. Through the induction of antitumor immune re­ mannose receptors on DCs, which facilitate antigen internalization by
sponses in vivo and thereversal of the immunosuppressive milieu, mannosylation. The same approach was successfully applied to a
CCM@ (PSiNPs@Au) prevented the metastasis of existing solid tumors dextran-based nanovaccine containing LPS. Compared with a mixture of
and demonstrated good biosafety, additionally acting as a photothermal soluble antigen and LPS, nanoformulations produced greater
agent to destroy these tumors. To create adjuvant-loaded tumor cell CD8 + T-cell responses that were robustly antigen-specific [335]. Li­
membrane-coated NPs, Kroll et al.[325] encapsulated CpG sequences in posomes conjugated with Langerin ligands demonstrated the efficient
biodegradable PLGA NPs and coated them with membranes produced targeting of Langerhans cells in human skin by focusing on Langerins
from mouse B16F10 melanoma cells. These NPs facilitated DC matura­ (CD207), which are only expressed in thesecells [336]. As an alternative
tion, stimulated the release of proinflammatory cytokines IL-6 and IL-12, to the typical MHC II presentation and CD4 + T-helper-cell activation
and were more easily endocytosed by DCs (Fig. 1). A vaccine composed pathway, DCs can process antigens and present them via the MHC I
of CCM-encapsulated PLGA NPs and the TLR7 agonist imiquimod was pathway, activating CD8 + T cells in aprocess that is known as cross­
developed by Xiao et al. [326]. In vitro research indicated that these presentation and proceeds via the cytosolic route.
vaccines enhanced DC maturation and increased the antitumor response Nanovaccines can modify intracellular antigen transport and cross-
against breast cancer 4T1 cells; however, in vivo research showed that presentation processes. Li et al. [337] and Jia et al. [338] demon­
these vaccines reduced tumor growth and prolonged survival. To strated that various NP types, including inorganic, polymeric, and lipid
simultaneously identify and remove tumors, Chen et al. [327] enclosed a NPs, can effectively stimulate CD8 + T-cell growth through antigen
tumor membrane in PLGA NPs (ICNPs) that contained indocyanine crosspresentation. Apolymeric microneedle containing encapsulated
green (ICG). Polyethylene glycol (PEG) was added to the cell membrane antigens was used to effectively target Langerhans cells [339].

14
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Fig. 6. Mechanism of action of nanovaccines. Antigen-presenting cells (APCs) are stimulated by various types of NP-attached antigens to process and deliver these
antigens in various ways. These antigens are subsequentlydestroyed by the APCs and then presented by MHC I or MHCII. In thisprocess, the APCs also secrete
cytokines, thus modifying the cytokine milieu and determiningwhether an inflammatory response is pro- or anti-inflammatory. The clonal proliferation of the
stimulated T and B cells enhances the immunological response. Antibodies are released by activated plasma B cells in response to the particular NP-coupled antigen
(created with Biorender.com).

Cross-presentation depends on particle–antigen linkage, and disulfide and biodegradable nanoparticles, which can improve their stability and
bonding between NPs and antigens causes antigen release into the biodistribution, reduce the possibility of off-target effects, and enable
endosomal compartment, which, in turn causes the expansion of controlled and prolonged release at the tumor site, is one possible
CD8 + T-cells, as opposed to nondegradable linkers. Nanovaccines can avenue for delivery. The design of nanovaccines should focus on maxi­
induce humoral and cell-mediated immune responses. B cells, which mizing selectivity and efficacy and customizing vaccines to each pa­
control antibody generation, must be continuously and repeatedly tient’s tumor features. The creation of customized nanovaccines will
activated to produce humoral responses (Fig. 6). Compared with soluble offer cancer patients a long-lasting and efficient treatment, enhancing
antigens, calcium phosphate NPs with covalently surface-bound anti­ their prognosis and life quality. Targeted protein degradation and
gens exhibited a considerably higher level of B cell activation. Compared nanotechnology can beused to create personalized cancer nanovaccines,
to the encapsulated antigen, the antigen on the surface of multilamellar which offer extremely effective, patient-specific, and selective thera­
vesicles elicited a stronger humoral reaction. Multivalent antigen pre­ peutics. By permitting the degradation of the hitherto undruggable
sentation, which can be accomplished using NP systems, can also elevate targets, lowering systemic toxicity, and boosting the immune response
antigen-specific antibody levels. Self-assembling NPs were created by against cancer cells, this strategy may overcome the drawbacks of
Ueda et al. to develop the best geometry for the multivalent presentation existing treatments.
of viral glycoproteins [340].
9. Conclusion and future perspectives
8. Cancer nanovaccines: safety, innovation and mitigation
strategies Numerous cancer immunotherapy methods have been studied,
including adoptive cell transfer therapy, immune checkpoint inhibition,
Side effects or toxicity can have grave consequences, particularly cancer therapeutic vaccines, and oncolytic virotherapy. Cancer thera­
when it comes to therapies for serious illnesses like cancer. Hence, peutic vaccines can substantially improve local and/or immunosup­
thorough preclinical investigations incorporating animal models are pression and stimulate cancer-specific immune responses. These
essential for safety profile evaluation prior to human clinical trials. The characteristic features may help overcome the problems of current im­
safety issues to be addressed includespecificity concerns, linker, un­ munotherapies, such as low response rates and immune-related side
foreseen cell signaling disruptions, overloading of cellular degradation effects. The promise of nanovaccines lies in increasing the effectiveness
machinery, immunological responses, biodistribution and pharmacoki­ of cancer therapeutic vaccines. The immunogenicity of molecular vac­
netics, long-term effects, and resistance development. Precision medi­ cines can be greatly increased using nanovaccines, which effectively
cine has been made possible by the special advantages of nanovaccines, codeliver multivalent molecular antigens and adjuvants into lymphoid
such as increased specificity, efficiency, and multifunctionality as well tissues and immune cells to enhance antigen-specific adaptive immune
as the possibility of personalized treatment. The use of biocompatible responses during cancer therapy. Various nanovaccines have been

15
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

created and evaluated in preclinical models and occasionally in humans Declaration of Competing Interest
for cancer immunotherapy by combining various nanoengineering
techniques. Cancer nanovaccines can effectively treat tumors through The authors declare the following financial interests/personal re­
the proper delivery of tumor antigens to APCs, which leads to the lationships which may be considered as potential competing interests:
maturation and activation of these cells, increases the infiltration of The authors declare that they have no known competing financial in­
antitumor functional CD8 + T cells, facilitates the activation of DCs and terests or personal relationships that could have appeared to influence
formation of antigen depots, and maintains stability, thus helping to the work reported in this paper.
maximize the potential of cancer therapeutic vaccines. In this review, we
discussed the recent advances in nanocarrier types, nanoplatforms, and Data Availability
nanovaccines, including cancer neoantigen nanovaccines, STING-
activating nanovaccines, artificial antigen-presenting cells, and mRNA No data was used for the research described in the article.
nanovaccines. Furthermore, we focused ontumor cell–derived vaccines,
including wholetumor cell components, EVs, and cell mem­ Acknowledgements
brane–encapsulated NPs. Tumor cell–derived vaccines contain multiple
tumor antigens that can induce extensive and potent immune responses. We would have never been able to complete this review without the
These newly emerging nanovaccine strategies mayhelp revolutionize or people who have contributed to cancer immunotherapy and cancer
supplement the landscape of cancer immunotherapy. nanovaccines and owe our gratitude to them. We have cited as many
Although nanovaccines have shown considerable promise for cancer references as permitted and apologize to the authors of publications we
immunotherapy, researchers still need toincrease the immunogenicity of have not cited because of the above limitation.
antigens, counter the immune escape mechanism of tumors, and achieve This study was supported by BiOrgan Solution Ltd., Seoul, Republic
the effective delivery of tumor vaccines. Over the past decade, tumor of Korea.
cell–derived vaccines have been usedto improve the long-term immune
memory effect against cancer, attracting considerable attention. Several References
research groups have reported encouraging preclinical results. The best
vaccine candidates were determined by the comprehensive regulation of [1] H. Sung, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 71
NPs. Thus, future studies should consider the benefits of NPs with (3) (2021) 209–249.
adjustable properties for nanovaccine design. Future vaccination is ex­ [2] R.L. Siegel, et al., Cancer Statistics, 2021, CA Cancer J. Clin. 71 (1) (2021) 7–33.
pected to depend on the development of stable, safe, and individualized [3] F. Bray, et al., The ever-increasing importance of cancer as a leading cause of
premature death worldwide, Cancer 127 (16) (2021) 3029–3030.
nanovaccines guaranteeing strong and lasting antitumor immune [4] Y. Li, et al., Targeting lymph node delivery with nanovaccines for cancer
responses. immunotherapy: recent advances and future directions, J. Nanobiotechnol. 21 (1)
The immunogenicity of tumor vaccines can be enhanced using ge­ (2023), 212.
[5] I. Mellman, G. Coukos, G. Dranoff, Cancer immunotherapy comes of age, Nature
netic, chemical, and nanoengineering techniques. Tumor cell–derived 480 (7378) (2011) 480–489.
vaccines include a large variety of antigens; however, their capacity to [6] R. Goforth, et al., Immune stimulatory antigen loaded particles combined with
trigger tumor immunogenicity requires considerable improvement. A depletion of regulatory T-cells induce potent tumor specific immunity in a mouse
model of melanoma, Cancer Immunol. Immunother. 58 (4) (2009) 517–530.
deeper understanding of the interactions between cell-specific mole­
[7] Y. Krishnamachari, A.K. Salem, Innovative strategies for co-delivering antigens
cules on exosomes and immune cells as well as tumor cells will help lay and CpG oligonucleotides, Adv. Drug Deliv. Rev. 61 (3) (2009) 205–217.
the groundwork for the development of new exosome-based biomarkers [8] J.N. Blattman, P.D. Greenberg, Cancer immunotherapy: a treatment for the
and efficient drugs for cancer immunotherapy. This is especially true for masses, Science 305 (5681) (2004) 200–205.
[9] J. Diebold, et al., Diagnostic and molecular genetic pathology of serous
tumor vaccines made from EVs such as OMVs and exosomes. Regarding borderline tumours of the ovary, Curr. Diagn. Pathol. 10 (4) (2004) 318–325.
characterization, purification, fabrication, and scale-up manufacturing, [10] C.J. Melief, Cancer: immune pact with the enemy, Nature 450 (7171) (2007)
TEVs must overcome several obstacles, primarily thoseassociated with 803–804.
[11] N. Williams, Tumor cells fight back to beat immune system, Science 274 (5291)
EV differentiation and isolation. In terms of size, TMVs and TEXs are (1996) 1302.
comparable, and no standardized biomarker fordistinguishing TEV iso­ [12] X. Cai, L. Zhang, W. Wei, Regulatory B cells in inflammatory diseases and tumor,
forms is available. Therefore, their isolation makes it difficult to assess Int. Immunopharmacol. 67 (2019) 281–286.
[13] Y. Zhang, et al., Nanovaccines for cancer immunotherapy, Wiley Inter. Rev.
the clinical efficacy of vaccines. EVs can only be accurately isolated Nanomed. Nanobiotechnol. 11 (5) (2019), e1559.
once; subsequently, we can learn about each subpopulation’s features [14] L. Qin, et al., Nanovaccine-Based Strategies to Overcome Challenges in the Whole
and labeling as well as the function of each subgroup in cellular Vaccination Cascade for Tumor Immunotherapy, Small 17 (28) (2021),
e2006000.
communication and physiological processes. Before EV vaccines can be [15] Y. Zhao, et al., Nanoparticle delivery of CDDO-Me remodels the tumor
formally utilized in clinical applications, quality categorization and microenvironment and enhances vaccine therapy for melanoma, Biomaterials 68
standards for biopharmaceuticals should be addressed. At the earliest (2015) 54–66.
[16] N. El-Sayed, et al., Functionalized multifunctional nanovaccine for targeting
opportunity, the FDA should adopt special GMP requirements to guar­
dendritic cells and modulation of immune response, Int. J. Pharm. 593 (2021),
antee the safety of exosome treatments. EV quality management has 120123.
already been attempted, and several studies have revealed methods for [17] R. Hu, et al., Core-shell magnetic gold nanoparticles for magnetic field-enhanced
boosting exosome production. Future advancements in engineering radio-photothermal therapy in cervical cancer, Nanomaterials 7 (5) (2017).
[18] H. Kim, et al., Combination of sunitinib and PD-L1 blockade enhances anticancer
tools may result in TEVs eliciting more potent antitumor immune re­ efficacy of TLR7/8 agonist-based nanovaccine, Mol. Pharm. 16 (3) (2019)
sponses, and the integration of clinical data with cutting-edge technol­ 1200–1210.
ogy will lay the groundwork for TEV manufacturing and clinical use. [19] X. Du, et al., A tumor-targeted, intracellular activatable and theranostic nanodiamond
drug platform for strongly enhanced in vivo antitumor therapy, J. Mater. Chem. B 8
(8) (2020) 1660–1671.
CRediT authorship contribution statement [20] T. Cai, et al., Delivery of nanovaccine towards lymphoid organs: recent strategies
in enhancing cancer immunotherapy, J. Nanobiotechnol. 19 (1) (2021), 389.
[21] P. Bhardwaj, et al., Advancements in prophylactic and therapeutic nanovaccines,
Gurunathan Sangiliyandi: Conceptualization, Writing – original Acta Biomater. 108 (2020) 1–21.
draft, Writing – review & editing. Wang Lin: Methodology, Software. [22] S.M. Gheibi Hayat, M. Darroudi, Nanovaccine: a novel approach in immunization,
Thangaraj Pratheep: Methodology, Software. Kim Jin-Hoi: Concep­ J. Cell. Physiol. 234 (8) (2019) 12530–12536.
[23] Y. Gao, et al., pH/redox dual-responsive polyplex with effective endosomal
tualization, Funding acquisition, Project administration, Validation, escape for codelivery of siRNA and doxorubicin against drug-resistant cancer
Writing – original draft. Cao Qilong: Methodology, Software. cells, ACS Appl. Mater. Interfaces 11 (18) (2019) 16296–16310. Lu, R., et al.,

16
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

Inflammation-related cytokines in oral lichen planus: an overview. J Oral Pathol Med, [61] G.M. Lynn, et al., In vivo characterization of the physicochemical properties of
2015. 44(1): p. 1-14. polymer-linked TLR agonists that enhance vaccine immunogenicity, Nat. Biotechnol.
[24] U. Gazi, L. Martinez-Pomares, Influence of the mannose receptor in host immune 33 (11) (2015) 1201–1210.
responses, Immunobiology 214 (7) (2009) 554–561. [62] S.W. Kim, et al., Mutual destruction of deep lung tumor tissues by nanodrug-
[25] R. Lu, et al., Inflammation-related cytokines in oral lichen planus: an overview, conjugated stealth mesenchymal stem cells, Adv. Sci. 5 (5) (2018) 1700860.
J. Oral Pathol. Med. 44 (1) (2015) 1–14. [63] S.A. Rosenberg, N.P. Restifo, Adoptive cell transfer as personalized
[26] A. Alloatti, et al., Evaluation of cross-presentation in bone marrow-derived dendritic immunotherapy for human cancer, Science 348 (6230) (2015) 62–68.
cells, Bio Protoc. 6 (22) (2016). [64] S.L. Topalian, C.G. Drake, D.M. Pardoll, Immune checkpoint blockade: a common
[27] M. Embgenbroich, S. Burgdorf, Current concepts of antigen cross-presentation, denominator approach to cancer therapy, Cancer Cell 27 (4) (2015) 450–461.
Front Immunol. 9 (2018) 1643. [65] M. Wilhelm, et al., Prospective, multicenter study of 5-fluorouracil therapeutic
[28] M.O. Li, et al., Transforming growth factor-beta regulation of immune responses, drug monitoring in metastatic colorectal cancer treated in routine clinical
Annu Rev. Immunol. 24 (2006) 99–146. practice, Clin. Colorectal Cancer 15 (4) (2016) 381–388.
[29] S. Jain, et al., Mannosylated niosomes as adjuvant-carrier system for oral genetic [66] S. Barua, S. Mitragotri, Challenges associated with penetration of nanoparticles
immunization against hepatitis B, Immunol. Lett. 101 (1) (2005) 41–49. across cell and tissue barriers: a review of current status and future prospects,
[30] M. Zaric, et al., Dissolving microneedle delivery of nanoparticle-encapsulated Nano Today 9 (2) (2014) 223–243.
antigen elicits efficient cross-priming and Th1 immune responses by murine [67] G. Raposo, W. Stoorvogel, Extracellular vesicles: exosomes, microvesicles, and
Langerhans cells, J. Investig. Dermatol. 135 (2) (2015) 425–434. friends, J. Cell Biol. 200 (4) (2013) 373–383.
[31] C.S. Carson, et al., A nanovaccine for enhancing cellular immunity via cytosolic [68] L. Macia, et al., Host- and microbiota-derived extracellular vesicles, immune
co-delivery of antigen and polyIC RNA, J. Control Release 345 (2022) 354–370. function, and disease development, Int. J. Mol. Sci. 21 (1) (2019).
[32] J. Wolchok, Putting the immunologic brakes on cancer, Cell 175 (6) (2018) [69] S. Hayashi, et al., A comparison of the concentrations of C-reactive protein and
1452–1454. alpha1-acid glycoprotein in the serum of young and adult dogs with acute
[33] M.M. Riley, et al., The clinical application of tumor treating fields therapy in inflammation, Vet. Res. Commun. 25 (2) (2001) 117–126.
glioblastoma, J. Vis. Exp. (146) (2019). [70] N.N. Kuzmich, et al., TLR4 signaling pathway modulators as potential
[34] M. Ma, et al., Immunotherapy in anaplastic thyroid cancer, Am. J. Transl. Res. 12 therapeutics in inflammation and sepsis, Vaccines 5 (4) (2017).
(3) (2020) 974–988. [71] X. Gao, et al., Bacterial outer membrane vesicle-based cancer nanovaccines,
[35] C. Robert, A decade of immune-checkpoint inhibitors in cancer therapy, Nat. Cancer Biol. Med. 19 (9) (2022) 1290–1300.
Commun. 11 (1) (2020) 3801. [72] F. Mancini, et al., OMV vaccines and the role of TLR agonists in immune response,
[36] N. Abd-Aziz, C.L. Poh, Development of oncolytic viruses for cancer therapy, Int. J. Mol. Sci. 21 (12) (2020).
Transl. Res. 237 (2021) 98–123. [73] T. Schetters, Mechanisms involved in the persistence of babesia canis infection in
[37] U. Sahin, Ö. Türeci, Personalized vaccines for cancer immunotherapy, Science dogs, Pathogens 8 (3) (2019).
359 (6382) (2018) 1355–1360. [74] Y. Cheng, et al., Apigenin inhibits the growth of colorectal cancer through down-
[38] Y. Zhou, et al., Vaccine efficacy against primary and metastatic cancer with in vitro- regulation of E2F1/3 by miRNA-215-5p, Phytomedicine 89 (2021), 153603.
generated CD103, J. Immunother. Cancer 8 (1) (2020). [75] M. Li, et al., Bacterial outer membrane vesicles as a platform for biomedical
[39] L. Zhao, et al., Late-stage tumors induce anemia and immunosuppressive applications: an update, J. Control. Release 323 (2020) 253–268.
extramedullary erythroid progenitor cells, Nat. Med 24 (10) (2018) 1536–1544. [76] O.Y. Kim, et al., Bacterial outer membrane vesicles suppress tumor by interferon-
[40] I. Rana, et al., Nanocarriers for cancer nano-immunotherapy, Drug Deliv. Transl. γ-mediated antitumor response, Nat. Commun. 8 (1) (2017) 626.
Res 13 (7) (2023) 1936–1954. [77] C. Chen, et al., Isolation of a novel bacterial strain capable of producing abundant
[41] J. Cai, et al., Improving Cancer Vaccine Efficiency by Nanomedicine, Adv. extracellular membrane vesicles carrying a single major cargo protein and
Biosyst. 3 (3) (2019), e1800287. analysis of its transport mechanism, Front. Microbiol. 10 (2019) 3001.
[42] G. Zhu, et al., Intertwining DNA-RNA nanocapsules loaded with tumor [78] T. Yang, et al., Exosome delivered anticancer drugs across the blood-brain barrier
neoantigens as synergistic nanovaccines for cancer immunotherapy, Nat. for brain cancer therapy in Danio rerio, Pharm. Res. 32 (6) (2015) 2003–2014.
Commun. 8 (1) (2017) 1482. [79] J. Yang, et al., Exosome mediated delivery of miR-124 promotes neurogenesis
[43] A. Das, N. Ali, Nanovaccine: an emerging strategy, Expert Rev. Vaccin. 20 (10) after ischemia, Mol. Ther. Nucleic Acids 7 (2017) 278–287.
(2021) 1273–1290. [80] I. Manna, et al., Exosomal miRNA as peripheral biomarkers in Parkinson’s disease
[44] G. Alatrash, et al., Fucosylation enhances the efficacy of adoptively transferred and progressive supranuclear palsy: a pilot study, Park. Relat. Disord. 93 (2021)
antigen-specific cytotoxic T lymphocytes, Clin. Cancer Res. 25 (8) (2019) 77–84.
2610–2620. [81] R. Munagala, F. Aqil, R.C. Gupta, Exosomal miRNAs as biomarkers of recurrent
[45] D. Fioretti, et al., DNA vaccines: developing new strategies against cancer, lung cancer, Tumour Biol. 37 (8) (2016) 10703–10714.
J. Biomed. Biotechnol. 2010 (2010), 174378. [82] M. Katakowski, et al., Exosomes from marrow stromal cells expressing miR-146b
[46] P. Van Der Bruggen, et al., Tumor-specific shared antigenic peptides recognized inhibit glioma growth, Cancer Lett. 335 (1) (2013) 201–204.
by human T cells, Immunol. Rev. 188 (2002) 51–64. [83] C. Théry, L. Zitvogel, S. Amigorena, Exosomes: composition, biogenesis and
[47] V.E. Schijns, Mechanisms of vaccine adjuvant activity: initiation and regulation of function, Nat. Rev. Immunol. 2 (8) (2002) 569–579.
immune responses by vaccine adjuvants, Vaccine 21 (9–10) (2003) 829–831. [84] C.H. Tan, et al., Gastric cancer: Patterns of disease spread via the perigastric
[48] D. Felnerova, et al., Liposomes and virosomes as delivery systems for antigens, ligaments shown by CT, AJR Am. J. Roentgenol. 195 (2) (2010) 398–404.
nucleic acids and drugs, Curr. Opin. Biotechnol. 15 (6) (2004) 518–529. [85] Y.K. Lee, et al., Proinflammatory T-cell responses to gut microbiota promote
[49] R. Schwaninger, et al., Virosomes as new carrier system for cancer vaccines, experimental autoimmune encephalomyelitis, Proc. Natl. Acad. Sci. USA 108
Cancer Immunol. Immunother. 53 (11) (2004) 1005–1017. Suppl 1 (Suppl 1) (2011) 4615–4622.
[50] S. Adams, Toll-like receptor agonists in cancer therapy, Immunotherapy 1 (6) [86] N.L. Syn, et al., De-novo and acquired resistance to immune checkpoint targeting,
(2009) 949–964. Lancet Oncol. 18 (12) (2017) e731–e741.
[51] S. Gnjatic, N.B. Sawhney, N. Bhardwaj, Toll-like receptor agonists: are they good [87] X. Chen, et al., A dual-adjuvant neoantigen nanovaccine loaded with imiquimod
adjuvants? Cancer J. 16 (4) (2010) 382–391. and magnesium enhances anti-tumor immune responses of melanoma, Biomater.
[52] C.J. Bishop, S.Y. Tzeng, J.J. Green, Degradable polymer-coated gold Sci. 10 (23) (2022) 6740–6748.
nanoparticles for co-delivery of DNA and siRNA, Acta Biomater. 11 (2015) [88] M. Kaparakis-Liaskos, R.L. Ferrero, Immune modulation by bacterial outer
393–403. membrane vesicles, Nat. Rev. Immunol. 15 (6) (2015) 375–387.
[53] N. Petrovsky, Comparative safety of vaccine adjuvants: a summary of current [89] L. Zhang, et al., Targeted codelivery of an antigen and dual agonists by hybrid
evidence and future needs, Drug Saf. 38 (11) (2015) 1059–1074. nanoparticles for enhanced cancer immunotherapy, Nano Lett. 19 (7) (2019)
[54] A. Akinc, G. Battaglia, Exploiting endocytosis for nanomedicines, Cold Spring 4237–4249.
Harb. Perspect. Biol. 5 (11) (2013) a016980. [90] Q. Gou, et al., Polymeric nanoassemblies entrapping curcumin overcome
[55] M.I. Uddin, et al., Real-time imaging of VCAM-1 mRNA in TNF-α activated retinal multidrug resistance in ovarian cancer, Colloids Surf. B Biointerfaces 126 (2015)
microvascular endothelial cells using antisense hairpin-DNA functionalized gold 26–34.
nanoparticles, Nanomedicine 14 (1) (2018) 63–71. [91] B.T. Luk, L. Zhang, Cell membrane-camouflaged nanoparticles for drug delivery,
[56] Y. Song, et al., Mesoporous silica nanoparticles for stimuli-responsive controlled J. Control. Release 220 (B) (2015) 600–607.
drug delivery: advances, challenges, and outlook, Int. J. Nanomed. 12 (2017) [92] P. Roy, R. Noad, Virus-like particles as a vaccine delivery system: myths and facts,
87–110. Hum. Vaccin 4 (1) (2008) 5–12.
[57] T.T. Smith, et al., In situ programming of leukaemia-specific T cells using synthetic [93] B. Bellier, et al., DNA vaccines expressing retrovirus-like particles are efficient
DNA nanocarriers, Nat. Nanotechnol. 12 (8) (2017) 813–820. immunogens to induce neutralizing antibodies, Vaccine 27 (42) (2009)
[58] R. Aalinkeel, et al., Nanotherapy silencing the interleukin-8 gene produces 5772–5780.
regression of prostate cancer by inhibition of angiogenesis, Immunology 148 (4) [94] P. Garrone, et al., A prime-boost strategy using virus-like particles pseudotyped
(2016) 387–406. for HCV proteins triggers broadly neutralizing antibodies in macaques, Sci.
[59] Q. Liu, et al., Nanocarrier-mediated chemo-immunotherapy arrested cancer Transl. Med. 3 (94) (2011), p. 94ra71.
progression and induced tumor dormancy in desmoplastic melanoma, ACS Nano [95] E. Baslé, N. Joubert, M. Pucheault, Protein chemical modification on endogenous
12 (8) (2018) 7812–7825. amino acids, Chem. Biol. 17 (3) (2010) 213–227.
[60] Y.H. Lai, et al., Dual-drug nanomedicine with hydrophilic F127-modified [96] I.C. Schneider, et al., Displaying tetra-membrane spanning claudins on enveloped
magnetic nanocarriers assembled in amphiphilic gelatin for enhanced penetration virus-like particles for cancer immunotherapy, Biotechnol. J. 13 (3) (2018),
and drug delivery in deep tumor tissue, Int. J. Nanomed. 13 (2018) 3011–3026. e1700345.

17
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

[97] M. Deschuyteneer, et al., Molecular and structural characterization of the L1 [133] T.D. de Gruijl, et al., Whole-cell cancer vaccination: from autologous to allogeneic
virus-like particles that are used as vaccine antigens in Cervarix™, the AS04- tumor- and dendritic cell-based vaccines, Cancer Immunol. Immunother. 57 (10)
adjuvanted HPV-16 and -18 cervical cancer vaccine, Hum. Vaccine 6 (5) (2010) (2008) 1569–1577.
407–419. [134] Y. Igarashi, T. Sasada, Cancer vaccines: toward the next breakthrough in cancer
[98] Y. Zaheer, et al., Protein based nanomedicine: Promising therapeutic modalities immunotherapy, J. Immunol. Res. 2020 (2020) 5825401.
against inflammatory disorders, Nano Sel. 3 (4) (2022) 733–750. [135] B. Yu, et al., A NF-κB-Based high-throughput screening for immune adjuvants and
[99] Y.B. Peng, et al., A multi-mitochondrial anticancer agent that selectively kills inhibitors, Inflammation 46 (2) (2023) 598–611.
cancer cells and overcomes drug resistance, ChemMedChem 12 (3) (2017) [136] P.M. Santos, L.H. Butterfield, Dendritic cell-based cancer vaccines, J. Immunol.
250–256. 200 (2) (2018) 443–449.
[100] W. Tian, et al., Self-powered nanoscale photodetectors, Small 13 (45) (2017). [137] A. Nelde, H.G. Rammensee, J.S. Walz, The peptide vaccine of the future, Mol. Cell
[101] G. Zhu, et al., Efficient nanovaccine delivery in cancer immunotherapy, ACS Nano Proteom. 20 (2021), 100022.
11 (3) (2017) 2387–2392. [138] L. Silfverdal, et al., Risk of invasive cervical cancer in relation to clinical
[102] C. Feng, et al., Emerging vaccine nanotechnology: from defense against infection investigation and treatment after abnormal cytology: a population-based case-
to sniping cancer, Acta Pharm. Sin. B 12 (5) (2022) 2206–2223. control study, Int. J. Cancer 129 (6) (2011) 1450–1458.
[103] R.H. Fang, et al., Cancer cell membrane-coated nanoparticles for anticancer [139] R.E. Hollingsworth, K. Jansen, Turning the corner on therapeutic cancer vaccines,
vaccination and drug delivery, Nano Lett. 14 (4) (2014) 2181–2188. NPJ Vaccin. 4 (2019) 7.
[104] H. Cao, et al., Liposomes coated with isolated macrophage membrane can target [140] C. Larocca, J. Schlom, Viral vector-based therapeutic cancer vaccines, Cancer J.
lung metastasis of breast cancer, ACS Nano 10 (8) (2016) 7738–7748. 17 (5) (2011) 359–371.
[105] R. Ignatius, et al., Presentation of proteins encapsulated in sterically stabilized [141] S.J. Paston, et al., Cancer vaccines, adjuvants, and delivery systems, Front.
liposomes by dendritic cells initiates CD8(+) T-cell responses in vivo, Blood 96 (10) Immunol. 12 (2021), 627932.
(2000) 3505–3513. [142] J. Santos Apolonio, et al., Oncolytic virus therapy in cancer: a current review,
[106] M. Taneichi, et al., Antigen chemically coupled to the surface of liposomes are World J. Virol. 10 (5) (2021) 229–255.
cross-presented to CD8+ T cells and induce potent antitumor immunity1, [143] L.H. Russell, et al., Autoxidation of gallic acid induces ROS-dependent death in
J. Immunol. 177 (4) (2006) 2324–2330. human prostate cancer LNCaP cells, Anticancer Res 32 (5) (2012) 1595–1602.
[107] D.J. Bacon, et al., DNA sequence and mutational analyses of the pVir plasmid of [144] R. Fu, et al., Avenanthramide A triggers potent ROS-mediated anti-tumor effects
Campylobacter jejuni 81-176, Infect. Immun. 70 (11) (2002) 6242–6250. in colorectal cancer by directly targeting DDX3, Cell Death Dis. 10 (8) (2019),
[108] A.J. Geall, et al., Nonviral delivery of self-amplifying RNA vaccines, Proc. Natl. 593.
Acad. Sci. USA 109 (36) (2012) 14604–14609. [145] S.J. Russell, G.N. Barber, Oncolytic viruses as antigen-agnostic cancer vaccines,
[109] D.P. Vangasseri, et al., Immunostimulation of dendritic cells by cationic Cancer Cell 33 (4) (2018) 599–605.
liposomes, Mol. Membr. Biol. 23 (5) (2006) 385–395. [146] Y. Liu, Y. Shen, B. Wei, The clinical risk factors of adenovirus pneumonia in
[110] W. Yan, W. Chen, L. Huang, Mechanism of adjuvant activity of cationic liposome: children based on the logistic regression model: correlation with lactate
phosphorylation of a MAP kinase, ERK and induction of chemokines, Mol. dehydrogenase, Int. J. Clin. Pract. 2022 (2022) 3001013.
Immunol. 44 (15) (2007) 3672–3681. [147] C.J. Melief, et al., Therapeutic cancer vaccines, J. Clin. Investig. 125 (9) (2015)
[111] R.P. Sah, et al., New insights into pancreatic cancer-induced paraneoplastic 3401–3412.
diabetes, Nat. Rev. Gastroenterol. Hepatol. 10 (7) (2013) 423–433. [148] Y.L. Vishweshwaraiah, N.V. Dokholyan, mRNA vaccines for cancer
[112] R. Rietscher, et al., Antigen delivery via hydrophilic PEG-b-PAGE-b-PLGA immunotherapy, Front. Immunol. 13 (2022) 1029069.
nanoparticles boosts vaccination induced T cell immunity, Eur. J. Pharm. [149] H.Y. Bai, et al., Eukaryotic initiation factor 5A2 contributes to the maintenance of
Biopharm. 102 (2016) 20–31. CD133(+) hepatocellular carcinoma cells via the c-Myc/microRNA-29b axis,
[113] W. Song, et al., Stable loading and delivery of disulfiram with mPEG-PLGA/PCL Stem Cells 36 (2) (2018) 180–191.
mixed nanoparticles for tumor therapy, Nanomedicine 12 (2) (2016) 377–386. [150] M.A. Kutzler, D.B. Weiner, DNA vaccines: ready for prime time? Nat. Rev. Genet.
[114] S. Ahn, et al., Gold nanoparticles displaying tumor-associated self-antigens as a 9 (10) (2008) 776–788.
potential vaccine for cancer immunotherapy, Adv. Health Mater. 3 (8) (2014) [151] C.L. Trimble, et al., Safety, efficacy, and immunogenicity of VGX-3100, a
1194–1199. therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6
[115] J. Meng, et al., Carbon nanotubes conjugated to tumor lysate protein enhance the and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-
efficacy of an antitumor immunotherapy, Small 4 (9) (2008) 1364–1370. blind, placebo-controlled phase 2b trial, Lancet 386 (10008) (2015) 2078–2088.
[116] A.F. Radovic-Moreno, et al., Immunomodulatory spherical nucleic acids, Proc. [152] Y.J. Choi, et al., A phase II, prospective, randomized, multicenter, open-label
Natl. Acad. Sci. USA 112 (13) (2015) 3892–3897. study of GX-188E, an HPV DNA vaccine, in patients with cervical intraepithelial
[117] G. Deng, et al., Aptamer-conjugated gold nanoparticles and their diagnostic and neoplasia 3, Clin. Cancer Res. 26 (7) (2020) 1616–1623.
therapeutic roles in cancer, Front. Bioeng. Biotechnol. 11 (2023) 1118546. [153] E.K. Duperret, et al., A synthetic DNA, multi-neoantigen vaccine drives
[118] W. Meng, et al., Evaluation of poly (glycerol-adipate) nanoparticle uptake in an in predominately MHC class I CD8, Cancer Immunol. Res. 7 (2) (2019) 174–182.
vitro 3-D brain tumor co-culture model, Exp. Biol. Med. 232 (8) (2007) 1100–1108. [154] F. Eriksson, et al., DNA vaccine coding for the rhesus prostate specific antigen
[119] V.E. Schijns, Immunological concepts of vaccine adjuvant activity, Curr. Opin. delivered by intradermal electroporation in patients with relapsed prostate
Immunol. 12 (4) (2000) 456–463. cancer, Vaccine 31 (37) (2013) 3843–3848.
[120] S.J. Duthie, Folic-acid-mediated inhibition of human colon-cancer cell growth, [155] V. Tiriveedhi, et al., Safety and preliminary evidence of biologic efficacy of a
Nutrition 17 (9) (2001) 736–737. mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer,
[121] T. Kawai, S. Akira, Signaling to NF-kappaB by Toll-like receptors, Trends Mol. Clin. Cancer Res. 20 (23) (2014) 5964–5975.
Med. 13 (11) (2007) 460–469. [156] J.B. Ulmer, et al., RNA-based vaccines, Vaccine 30 (30) (2012) 4414–4418.
[122] J. Zhao, G. Du, X. Sun, Tumor antigen-based nanovaccines for cancer [157] S. Wilgenhof, et al., A phase IB study on intravenous synthetic mRNA
immunotherapy: a review, J. Biomed. Nanotechnol. 17 (11) (2021) 2099–2113. electroporated dendritic cell immunotherapy in pretreated advanced melanoma
[123] Z. Liao, et al., Self-adjuvanting cancer nanovaccines, J. Nanobiotechnol. 20 (1) patients, Ann. Oncol. 24 (10) (2013) 2686–2693.
(2022), 345. [158] U. Sahin, et al., COVID-19 vaccine BNT162b1 elicits human antibody and T,
[124] C. Wang, et al., Self-adjuvanted nanovaccine for cancer immunotherapy: Role of Nature 586 (7830) (2020) 594–599.
lysosomal rupture-induced ROS in MHC class I antigen presentation, Biomaterials [159] Z. Deng, et al., mRNA vaccines: the dawn of a new era of cancer immunotherapy,
79 (2016) 88–100. Front. Immunol. 13 (2022), 887125.
[125] Z.-S. Wen, et al., Chitosan nanoparticles act as an adjuvant to promote both Th1 [160] B.D. Adams, et al., Targeting noncoding RNAs in disease, J. Clin. Investig. 127 (3)
and Th2 immune responses induced by ovalbumin in mice, Mar. Drugs 9 (6) (2017) 761–771.
(2011) 1038–1055. [161] C. Chakraborty, et al., Therapeutic miRNA and siRNA: moving from bench to
[126] F. Stieneker, J. Kreuter, J. Löwer, High antibody titres in mice with clinic as next generation medicine, Mol. Ther. Nucleic Acids 8 (2017) 132–143.
polymethylmethacrylate nanoparticles as adjuvant for HIV vaccines, AIDS 5 (4) [162] J.C. Kaczmarek, P.S. Kowalski, D.G. Anderson, Advances in the delivery of RNA
(1991) 431–435. therapeutics: from concept to clinical reality, Genome Med. 9 (1) (2017) 60.
[127] M. Li, K.J. Czymmek, C.P. Huang, Responses of Ceriodaphnia dubia to TiO2 and [163] R. Rupaimoole, F.J. Slack, MicroRNA therapeutics: towards a new era for the
Al2O3 nanoparticles: a dynamic nano-toxicity assessment of energy budget management of cancer and other diseases, Nat. Rev. Drug Discov. 16 (3) (2017)
distribution, J. Hazard. Mater. 187 (1–3) (2011) 502–508. 203–222.
[128] S. Abdulnasser Harfoush, et al., High-dose intranasal application of titanium [164] B.S. Zhao, I.A. Roundtree, C. He, Post-transcriptional gene regulation by mRNA
dioxide nanoparticles induces the systemic uptakes and allergic airway modifications, Nat. Rev. Mol. Cell Biol. 18 (1) (2017) 31–42.
inflammation in asthmatic mice, Respir. Res. 21 (1) (2020), 168. [165] H. Mirzaei, et al., MicroRNA: Relevance to stroke diagnosis, prognosis, and
[129] J. Wolfram, et al., Safety of nanoparticles in medicine, Curr. Drug Targets 16 (14) therapy, J. Cell Physiol. 233 (2) (2018) 856–865.
(2015) 1671–1681. [166] D. Rosenblum, et al., Progress and challenges towards targeted delivery of cancer
[130] V. Karpisheh, et al., EP4 receptor as a novel promising therapeutic target in colon therapeutics, Nat. Commun. 9 (1) (2018) 1410.
cancer, Pathol. Res Pr. 216 (12) (2020), 153247. [167] B. Zhou, J.-W. Yu, A novel identified circular RNA, circRNA_010567, promotes
[131] J.M. Vyas, A.G. Van der Veen, H.L. Ploegh, The known unknowns of antigen myocardial fibrosis via suppressing miR-141 by targeting TGF-β1, Biochem.
processing and presentation, Nat. Rev. Immunol. 8 (8) (2008) 607–618. Biophys. Res. Commun. 487 (4) (2017) 769–775.
[132] C.L. Chiang, G. Coukos, L.E. Kandalaft, Whole tumor antigen vaccines: where are [168] Y. Lin, et al., Identification of key MicroRNAs and mechanisms in prostate cancer
we? Vaccines 3 (2) (2015) 344–372. evolution based on biomarker prioritization model and carcinogenic survey,
Front. Genet. 11 (2020), 596826.

18
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

[169] L. Tan, X. Sun, Recent advances in mRNA vaccine delivery, Nano Res. 11 (10) [206] D.L. Burdette, R.E. Vance, STING and the innate immune response to nucleic acids
(2018) 5338–5354. in the cytosol, Nat. Immunol. 14 (1) (2013) 19–26.
[170] A. Lundqvist, P. Pisa, Gene-modified dendritic cells for immunotherapy against [207] D. Shae, et al., Endosomolytic polymersomes increase the activity of cyclic
cancer, Med Oncol. 19 (4) (2002) 197–211. dinucleotide STING agonists to enhance cancer immunotherapy, Nat.
[171] A. Matsui, et al., Messenger RNA-based therapeutics for the treatment of Nanotechnol. 14 (3) (2019) 269–278.
apoptosis-associated diseases, Sci. Rep. 5 (2015) 15810. [208] M. Luo, et al., A STING-activating nanovaccine for cancer immunotherapy, Nat.
[172] L. Aagaard, J.J. Rossi, RNAi therapeutics: principles, prospects and challenges, Nanotechnol. 12 (7) (2017) 648–654.
Adv. Drug Deliv. Rev. 59 (2–3) (2007) 75–86. [209] L. Zitvogel, et al., Type I interferons in anticancer immunity, Nat. Rev. Immunol.
[173] L.M. Iyer, et al., Lineage-specific expansions of TET/JBP genes and a new class of 15 (7) (2015) 405–414.
DNA transposons shape fungal genomic and epigenetic landscapes, Proc. Natl. [210] S. Hervas-Stubbs, et al., Direct effects of type I interferons on cells of the immune
Acad. Sci. USA 111 (5) (2014) 1676–1683. system, Clin. Cancer Res. 17 (9) (2011) 2619–2627.
[174] F. Chen, M. Alphonse, Q. Liu, Strategies for nonviral nanoparticle-based delivery [211] M. Montoya, et al., Type I interferons produced by dendritic cells promote their
of CRISPR/Cas9 therapeutics, Wiley Inter. Rev. Nanomed. Nanobiotechnol. 12 (3) phenotypic and functional activation, Blood 99 (9) (2002) 3263–3271.
(2020), e1609. [212] M.S. Diamond, et al., Type I interferon is selectively required by dendritic cells for
[175] K.A. Hajj, K.A. Whitehead, Tools for translation: non-viral materials for immune rejection of tumors, J. Exp. Med. 208 (10) (2011) 1989–2003.
therapeutic mRNA delivery, Nat. Rev. Mater. 2 (10) (2017) 17056. [213] B.N. Bidwell, et al., Silencing of Irf7 pathways in breast cancer cells promotes
[176] S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug bone metastasis through immune escape, Nat. Med. 18 (8) (2012) 1224–1231.
delivery, Nat. Mater. 12 (11) (2013) 991–1003. [214] J. Yang, J. Yan, B. Liu, Targeting VEGF/VEGFR to modulate antitumor immunity,
[177] Q. Xiong, et al., Biomedical applications of mRNA nanomedicine, Nano Res. 11 Front. Immunol. 9 (2018) 978.
(10) (2018) 5281–5309. [215] K. Kiwerska, K. Szyfter, DNA repair in cancer initiation, progression, and therapy-
[178] C.V. Pecot, et al., RNA interference in the clinic: challenges and future directions, a double-edged sword, J. Appl. Genet. 60 (3–4) (2019) 329–334.
Nat. Rev. Cancer 11 (1) (2011) 59–67. [216] S. Bhattacharya, et al., RAD51 interconnects between DNA replication, DNA
[179] H. Zhang, et al., Delivery of mRNA vaccine with a lipid-like material potentiates repair and immunity, Nucleic Acids Res. 45 (8) (2017) 4590–4605.
antitumor efficacy through Toll-like receptor 4 signaling, Proc. Natl. Acad. Sci. [217] J. Guan, et al., MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1
USA 118 (6) (2021). activates the cGAS-STING pathway, Cancer Cell 39 (1) (2021) 109–121.e5.
[180] T.N. Schumacher, W. Scheper, P. Kvistborg, Cancer neoantigens, Annu. Rev. [218] F. Talens, M.A.T.M. Van Vugt, Inflammatory signaling in genomically instable
Immunol. 37 (2019) 173–200. cancers, Cell Cycle 18 (16) (2019) 1830–1848.
[181] A.H. Pearlman, et al., Targeting public neoantigens for cancer immunotherapy, [219] T. Reisländer, F.J. Groelly, M. Tarsounas, DNA damage and cancer
Nat. Cancer 2 (5) (2021) 487–497. immunotherapy: a STING in the tale, Mol. Cell 80 (1) (2020) 21–28.
[182] Z. Zhang, et al., Neoantigen: a new breakthrough in tumor immunotherapy, [220] H. Yang, et al., STING activation reprograms tumor vasculatures and synergizes
Front. Immunol. 12 (2021), 672356. with VEGFR2 blockade, J. Clin. Investig. 129 (10) (2019) 4350–4364.
[183] E. Wang, I. Aifantis, RNA splicing and cancer, Trends Cancer 6 (8) (2020) [221] B.C. Baguley, Antivascular therapy of cancer: DMXAA, Lancet Oncol. 4 (3) (2003)
631–644. 141–148.
[184] Z. Wang, Y.J. Cao, Adoptive cell therapy targeting neoantigens: a frontier for [222] K.E. Matthews, et al., 5,6-Dimethylxanthenone-4-acetic acid treatment of a non-
cancer research, Front. Immunol. 11 (2020) 176. immunogenic tumour does not synergize with active or passive CD8+ T-cell
[185] M. Efremova, et al., Neoantigens generated by individual mutations and their role immunotherapy, Immunol. Cell Biol. 84 (4) (2006) 383–389.
in cancer immunity and immunotherapy, Front. Immunol. 8 (2017) 1679. [223] M. Chelvanambi, et al., STING agonist-based treatment promotes vascular
[186] E. Blass, P.A. Ott, Advances in the development of personalized neoantigen-based normalization and tertiary lymphoid structure formation in the therapeutic
therapeutic cancer vaccines, Nat. Rev. Clin. Oncol. 18 (4) (2021) 215–229. melanoma microenvironment, J. Immunother. Cancer 9 (2) (2021).
[187] Y. Chu, et al., Lymph node-targeted neoantigen nanovaccines potentiate anti- [224] O. Demaria, et al., STING activation of tumor endothelial cells initiates
tumor immune responses of post-surgical melanoma, J. Nanobiotechnol. 20 (1) spontaneous and therapeutic antitumor immunity, Proc. Natl. Acad. Sci. USA 112
(2022) 190. (50) (2015) 15408–15413.
[188] E. Tran, P.F. Robbins, S.A. Rosenberg, Final common pathway’ of human cancer [225] J. Banchereau, A.K. Palucka, Dendritic cells as therapeutic vaccines against
immunotherapy: targeting random somatic mutations, Nat. Immunol. 18 (3) cancer, Nat. Rev. Immunol. 5 (4) (2005) 296–306.
(2017) 255–262. [226] D. Rodríguez-Pinto, B cells as antigen presenting cells, Cell. Immunol. 238 (2)
[189] M. Yarchoan, et al., Targeting neoantigens to augment antitumour immunity, Nat. (2005) 67–75.
Rev. Cancer 17 (9) (2017) 569. [227] S. Bal, G. Williams, M. Ray, A case of follicular small cleaved cell lymphoma with
[190] A.D. Wagner, et al., EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of t(14;18) and t(8;11), Cancer Genet. Cytogenet 48 (2) (1990) 199–201.
chemotherapy alone versus chemotherapy plus trastuzumab, versus [228] W. Zhang, et al., Phase I/II clinical trial of a Wilms’ tumor 1-targeted dendritic
chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment cell vaccination-based immunotherapy in patients with advanced cancer, Cancer
of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on Immunol. Immunother. 68 (1) (2019) 121–130.
pathologic response rate: a randomized phase II-intergroup trial of the EORTC- [229] T.W. Kim, et al., Enhancement of DNA vaccine potency by coadministration of a
Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch tumor antigen gene and DNA encoding serine protease inhibitor-6, Cancer Res. 64
Upper GI-Cancer group, BMC Cancer 19 (1) (2019), 494. (1) (2004) 400–405.
[191] A.E. Zamora, J.C. Crawford, P.G. Thomas, Hitting the target: how T cells detect [230] J.C. Sunshine, J.J. Green, Nanoengineering approaches to the design of artificial
and eliminate tumors, J. Immunol. 200 (2) (2018) 392–399. antigen-presenting cells, Nanomedicine 8 (7) (2013) 1173–1189.
[192] K. Pelletier, et al., CKD after 225Ac-PSMA617 therapy in patients with metastatic [231] L.J. Eggermont, et al., Towards efficient cancer immunotherapy: advances in
prostate cancer, Kidney Int. Rep. 6 (3) (2021) 853–856. developing artificial antigen-presenting cells, Trends Biotechnol. 32 (9) (2014)
[193] M. Yarchoan, A. Hopkins, E.M. Jaffee, Tumor mutational burden and response 456–465.
rate to PD-1 inhibition, New Engl. J. Med. 377 (25) (2017) 2500–2501. [232] K. Perica, et al., Enrichment and expansion with nanoscale artificial antigen
[194] T.N. Schumacher, R.D. Schreiber, Neoantigens in cancer immunotherapy, Science presenting cells for adoptive immunotherapy, ACS Nano 9 (7) (2015) 6861–6871.
348 (6230) (2015) 69–74. [233] R.A. Meyer, et al., Biodegradable nanoellipsoidal artificial antigen presenting
[195] X. Zhou, et al., Metal-phenolic network-encapsulated nanovaccine with ph and cells for antigen specific T-cell activation, Small 11 (13) (2015) 1519–1525.
reduction dual responsiveness for enhanced cancer immunotherapy, Mol. Pharm. [234] M.C. Milone, et al., Chimeric receptors containing CD137 signal transduction domains
17 (12) (2020) 4603–4615. mediate enhanced survival of T cells and increased antileukemic efficacy in vivo, Mol.
[196] C.A. Klebanoff, J.D. Wolchok, Shared cancer neoantigens: making private matters Ther. 17 (8) (2009) 1453–1464.
public, J. Exp. Med 215 (1) (2018) 5–7. [235] Y. Liu, et al., Soluble CD40 ligand-activated B cells from patients with chronic
[197] Ö. Türeci, et al., Challenges towards the realization of individualized cancer hepatitis B virus infection as antigen presenting cells to induce hepatitis B virus
vaccines, Nat. Biomed. Eng. 2 (8) (2018) 566–569. specific cytotoxic T lymphocytes, Biochem. Biophys. Res. Commun. 450 (1)
[198] A. Amouzegar, et al., STING agonists as cancer therapeutics, Cancers 13 (11) (2014) 61–66.
(2021). [236] C.J. Turtle, S.R. Riddell, Artificial antigen-presenting cells for use in adoptive
[199] Q. Chen, L. Sun, Z.J. Chen, Regulation and function of the cGAS-STING pathway immunotherapy, Cancer J. 16 (4) (2010) 374–381.
of cytosolic DNA sensing, Nat. Immunol. 17 (10) (2016) 1142–1149. [237] X. Zang, et al., Nanoparticles for tumor immunotherapy, Eur. J. Pharm.
[200] H. Ishikawa, Z. Ma, G.N. Barber, STING regulates intracellular DNA-mediated, Biopharm. 115 (2017) 243–256.
type I interferon-dependent innate immunity, Nature 461 (7265) (2009) [238] J.P. Fisher, et al., Neuroblastoma killing properties of Vδ2 and Vδ2-negative γδT
788–792. cells following expansion by artificial antigen-presenting cells, Clin. Cancer Res.
[201] S.L. Ng, et al., Type 1 conventional CD103, Front Immunol. 9 (2018) 3043. 20 (22) (2014) 5720–5732.
[202] S.K. Sundararaman, D.A. Barbie, Tumor cGAMP awakens the natural killers, [239] A.N. Hasan, et al., Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15
Immunity 49 (4) (2018) 585–587. complexes mediate proliferation of high-avidity central memory CD8, Clin. Exp.
[203] S.R. Woo, et al., STING-dependent cytosolic DNA sensing mediates innate Immunol. 186 (2) (2016) 249–265.
immune recognition of immunogenic tumors, Immunity 41 (5) (2014) 830–842. [240] J.W. Hickey, et al., Biologically inspired design of nanoparticle artificial antigen-
[204] M.C. Hanson, et al., Nanoparticulate STING agonists are potent lymph node- presenting cells for immunomodulation, Nano Lett. 17 (11) (2017) 7045–7054.
targeted vaccine adjuvants, J. Clin. Invest 125 (6) (2015) 2532–2546. [241] A.L. Siefert, T.M. Fahmy, D. Kim, Artificial antigen-presenting cells for
[205] J. Jiang, Y. Zhan, J. Li, The role of the key differentially mutated gene FGFR3 in immunotherapies, Methods Mol. Biol. 1530 (2017) 343–353.
the immune microenvironment of bladder cancer, J. Immunol. Res. 2022 (2022)
7952706.

19
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

[242] X. Zhang, et al., CD16 CAR-T cells enhance antitumor activity of CpG ODN-loaded [276] L. Miao, et al., Delivery of mRNA vaccines with heterocyclic lipids increases anti-
nanoparticle-adjuvanted tumor antigen-derived vaccinevia ADCC approach, tumor efficacy by STING-mediated immune cell activation, Nat. Biotechnol. 37
J. Nanobiotechnol. 21 (1) (2023), 159. (10) (2019) 1174–1185.
[243] S. Zhou, et al., Engineering ApoE3-incorporated biomimetic nanoparticle for [277] H. Naka, et al., Requirement for COUP-TFI and II in the temporal specification of
efficient vaccine delivery to dendritic cells via macropinocytosis to enhance neural stem cells in CNS development, Nat. Neurosci. 11 (9) (2008) 1014–1023.
cancer immunotherapy, Biomaterials 235 (2020), 119795. [278] Q. Zeng, et al., Preparation, characterization, and pharmacodynamic study on
[244] S. Ma, et al., Recognition of tumor-associated antigens and immune subtypes in deep second degree burns of total flavonoids composite phospholipids liposome
glioma for mRNA vaccine development, Front. Immunol. 12 (2021), 738435. gel of, Drug Dev. Ind. Pharm. 46 (12) (2020) 2000–2009.
[245] X. Qiu, J. Jia, Research advances on TCM anti-tumor effects and the molecular [279] E.J. Sayour, H.R. Mendez-Gomez, D.A. Mitchell, Cancer Vaccine Immunotherapy
mechanisms, J. Cancer Res. Ther. 10 Suppl 1 (2014) 8–13. with RNA-Loaded Liposomes, Int J. Mol. Sci. 19 (10) (2018).
[246] V. Pavot, et al., Cutting edge: new chimeric NOD2/TLR2 adjuvant drastically [280] W. Zhang, et al., The progress and perspective of nanoparticle-enabled tumor
increases vaccine immunogenicity, J. Immunol. 193 (12) (2014) 5781–5785. metastasis treatment, Acta Pharm. Sin. B 10 (11) (2020) 2037–2053.
[247] S. Qi, et al., Neutrophil infiltration and whole-cell vaccine elicited by N- [281] X. Zhang, et al., Engineered tumor cell-derived vaccines against cancer: The art of
dihydrogalactochitosan combined with NIR phototherapy to enhance antitumor combating poison with poison, Bioact. Mater. 22 (2023) 491–517.
immune response and T cell immune memory, Theranostics 10 (4) (2020) [282] S. Zhang, J. Yang, L. Shen, Extracellular vesicle-mediated regulation of tumor
1814–1832. angiogenesis- implications for anti-angiogenesis therapy, J. Cell. Mol. Med. 25 (6)
[248] J.L. Tanyi, et al., Personalized cancer vaccine effectively mobilizes antitumor T (2021) 2776–2785.
cell immunity in ovarian cancer, Sci. Transl. Med. 10 (436) (2018). [283] C. Théry, M. Ostrowski, E. Segura, Membrane vesicles as conveyors of immune
[249] S.G. Klochkov, et al., Implications of nanotechnology for the treatment of cancer: responses, Nat. Rev. Immunol. 9 (8) (2009) 581–593.
Recent advances, Semin Cancer Biol. 69 (2021) 190–199. [284] M. Li, et al., A biomimetic antitumor nanovaccine based on biocompatible
[250] J.Y. Jang, et al., Exosome derived from epigallocatechin gallate treated breast calcium pyrophosphate and tumor cell membrane antigens, Asian J. Pharm. Sci.
cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage 16 (1) (2021) 97–109.
infiltration and M2 polarization, BMC Cancer 13 (2013) 421. [285] P. Vader, et al., Extracellular vesicles for drug delivery, Adv. Drug Deliv. Rev. 106
[251] Y. Zhang, et al., Polymeric nanoparticle-based nanovaccines for cancer (Pt A) (2016) 148–156.
immunotherapy, Mater. Horiz. 10 (2) (2023) 361–392. [286] J.G. van den Boorn, et al., Exosomes as nucleic acid nanocarriers, Adv. Drug
[252] K.K. Dewangan, et al., Breast cancer diagnosis in an early stage using novel deep Deliv. Rev. 65 (3) (2013) 331–335.
learning with hybrid optimization technique, Multimed. Tools Appl. 81 (10) [287] L. Zhu, et al., Isolation and characterization of exosomes for cancer research,
(2022) 13935–13960. J. Hematol. Oncol. 13 (1) (2020), 152.
[253] X.L. Yu, et al., Vaccines targeting the primary amino acid sequence and [288] M. Naseri, et al., Tumor-derived exosomes: the next generation of promising cell-
conformational epitope of amyloid-β had distinct effects on neuropathology and free vaccines in cancer immunotherapy, Oncoimmunology 9 (1) (2020) 1779991.
cognitive deficits in EAE/AD mice, Br. J. Pharmacol. 177 (12) (2020) 2860–2871. [289] H. Chen, et al., Lewis X oligosaccharides-heparanase complex targeting to DCs
[254] G. Parmiani, et al., Autologous versus allogeneic cell-based vaccines? Cancer J. 17 enhance antitumor response in mice, Cell Immunol. 269 (2) (2011) 144–148.
(5) (2011) 331–336. [290] C. Huang, et al., Proteogenomic insights into the biology and treatment of HPV-
[255] S.L. Kurtz, S. Ravindranathan, D.A. Zaharoff, Current status of autologous breast negative head and neck squamous cell carcinoma, Cancer Cell 39 (3) (2021)
tumor cell-based vaccines, Expert Rev. Vaccin. 13 (12) (2014) 1439–1445. 361–379, e16.
[256] K.E. Wong, et al., Evaluation of PolyMPC-Dox prodrugs in a human ovarian tumor [291] Y.S. Lee, et al., Introduction of the CIITA gene into tumor cells produces exosomes
model, Mol. Pharm. 13 (5) (2016) 1679–1687. with enhanced anti-tumor effects, Exp. Mol. Med. 43 (5) (2011) 281–290.
[257] T. Tsujikawa, et al., Prognostic significance of spatial immune profiles in human [292] F. Fan, M. Zhou, Y. Luo, [Research update of anti-TNF-α biologic agents in the
solid cancers, Cancer Sci. 111 (10) (2020) 3426–3434. treatment of uveitis], Zhonghua Yan Ke Za Zhi 49 (3) (2013) 285–288.
[258] D. Alson, et al., Combination vaccination with tetanus toxoid and enhanced [293] J. Wolfers, et al., Tumor-derived exosomes are a source of shared tumor rejection
tumor-cell based vaccine against cervical cancer in a mouse model, Front. antigens for CTL cross-priming, Nat. Med 7 (3) (2001) 297–303.
Immunol. 11 (2020) 927. [294] Q. Rao, et al., Tumor-derived exosomes elicit tumor suppression in murine
[259] V.M. Kim, et al., Neoantigen-based EpiGVAX vaccine initiates antitumor hepatocellular carcinoma models and humans in vitro, Hepatology 64 (2) (2016)
immunity in colorectal cancer, JCI Insight 5 (9) (2020). 456–472.
[260] D.T. Le, et al., Safety and survival with GVAX pancreas prime and Listeria [295] X. Xia, et al., Porous silicon microparticle potentiates anti-tumor immunity by
Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic enhancing cross-presentation and inducing type I interferon response, Cell Rep.
pancreatic cancer, J. Clin. Oncol. 33 (12) (2015) 1325–1333. 11 (6) (2015) 957–966.
[261] F. Chen, et al., New horizons in tumor microenvironment biology: challenges and [296] L. Huang, et al., Engineered exosomes as an in situ DC-primed vaccine to boost
opportunities, BMC Med 13 (2015) 45. antitumor immunity in breast cancer, Mol. Cancer 21 (1) (2022), 45.
[262] X. Zhang, et al., MYC is downregulated by a mitochondrial checkpoint [297] R. Jaini, et al., An autoimmune-mediated strategy for prophylactic breast cancer
mechanism, Oncotarget 8 (52) (2017) 90225–90237. vaccination, Nat. Med 16 (7) (2010) 799–803.
[263] C. Berti, et al., Polymer nanoparticle-mediated delivery of oxidized tumor lysate- [298] J. Rossowska, et al., Antitumor potential of extracellular vesicles released by
based cancer vaccines, Macromol. Biosci. 22 (2) (2022), e2100356. genetically modified murine colon carcinoma cells with overexpression of
[264] M.A. Neller, J.A. López, C.W. Schmidt, Antigens for cancer immunotherapy, interleukin-12 and shRNA for TGF-β1, Front Immunol. 10 (2019) 211.
Semin Immunol. 20 (5) (2008) 286–295. [299] S. Ohno, et al., Systemically injected exosomes targeted to EGFR deliver
[265] L.J. Ochyl, J.J. Moon, Dendritic cell membrane vesicles for activation and antitumor microRNA to breast cancer cells, Mol. Ther. 21 (1) (2013) 185–191.
maintenance of antigen-specific T cells, Adv. Health Mater. 8 (4) (2019), [300] X. Qin, et al., Cell-Derived Biogenetic Gold Nanoparticles for Sensitizing
e1801091. Radiotherapy and Boosting Immune Response against Cancer, Small 17 (50)
[266] X. Wang, et al., Polydopamine nanoparticles carrying tumor cell lysate as a (2021), e2103984.
potential vaccine for colorectal cancer immunotherapy, Biomater. Sci. 7 (7) [301] X. Ren, et al., Paclitaxel suppresses proliferation and induces apoptosis through
(2019) 3062–3075. regulation of ROS and the AKT/MAPK signaling pathway in canine mammary
[267] Y. Han, X. Lu, G. Wang, STAT3 inhibitor enhances chemotherapy drug efficacy by gland tumor cells, Mol. Med. Rep. 17 (6) (2018) 8289–8299.
modulating mucin 1 expression in non-small cell lung carcinoma, Trop. J. Pharm. [302] S. Zhu, et al., Roles of microvesicles in tumor progression and clinical
Res. 16 (7) (2017) 1513–1521. applications, Int. J. Nanomed. 16 (2021) 7071–7090.
[268] S. Gurunathan, et al., Cytotoxicity of biologically synthesized silver nanoparticles [303] X. Bian, et al., Microvesicles and chemokines in tumor microenvironment:
in MDA-MB-231 human breast cancer cells, Biomed. Res Int 2013 (2013), mediators of intercellular communications in tumor progression, Mol. Cancer 18
535796. (1) (2019), 50.
[269] C.L. Chiang, et al., A dendritic cell vaccine pulsed with autologous hypochlorous [304] S. Gurunathan, et al., Mitochondrial peptide humanin protects silver
acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: nanoparticles-induced neurotoxicity in human neuroblastoma cancer cells (SH-
from bench to bedside, Clin. Cancer Res. 19 (17) (2013) 4801–4815. SY5Y), Int. J. Mol. Sci. 20 (18) (2019).
[270] G.N. Shi, et al., Enhanced antitumor immunity by targeting dendritic cells with [305] B. Pineda, et al., Malignant glioma therapy by vaccination with irradiated C6 cell-
tumor cell lysate-loaded chitosan nanoparticles vaccine, Biomaterials 113 (2017) derived microvesicles promotes an antitumoral immune response, Mol. Ther. 27
191–202. (9) (2019) 1612–1620.
[271] E.C. Carroll, et al., The vaccine adjuvant chitosan promotes cellular immunity via [306] H. Zhang, et al., Cell-free tumor microparticle vaccines stimulate dendritic cells
DNA sensor cGAS-STING-dependent induction of type i interferons, Immunity 44 via cGAS/STING signaling, Cancer Immunol. Res 3 (2) (2015) 196–205.
(3) (2016) 597–608. [307] H. Zhang, B. Huang, Tumor cell-derived microparticles: a new form of cancer
[272] L. Song, et al., Single component pluronic F127-lipoic acid hydrogels with self- vaccine, Oncoimmunology 4 (8) (2015), e1017704.
healing and multi-responsive properties, Eur. Polym. J. 115 (2019) 346–355. [308] J. Ma, et al., Mechanisms by which dendritic cells present tumor microparticle
[273] F.E. González, et al., Melanocortin 1 Receptor-derived peptides are efficiently antigens to CD8, Cancer Immunol. Res. 6 (9) (2018) 1057–1068.
recognized by cytotoxic T lymphocytes from melanoma patients, Immunobiology [309] W. Dong, et al., Oral delivery of tumor microparticle vaccines activates NOD2
219 (3) (2014) 189–197. signaling pathway in ileac epithelium rendering potent antitumor T cell
[274] J.D. Beck, et al., mRNA therapeutics in cancer immunotherapy, Mol. Cancer 20 immunity, Oncoimmunology 6 (3) (2017), e1282589.
(1) (2021) 69. [310] J. Chen, et al., Unbalanced glutamine partitioning between CD8T cells and cancer
[275] Z. Chen, et al., The structure of the MHC class i molecule of bony fishes provides cells accompanied by immune cell dysfunction in hepatocellular carcinoma, Cells
insights into the conserved nature of the antigen-presenting system, J. Immunol. 11 (23) (2022).
199 (10) (2017) 3668–3678.

20
S. Gurunathan et al. Biomedicine & Pharmacotherapy 170 (2024) 115992

[311] A.C. Parenky, et al., Harnessing T-cell activity against prostate cancer: a [326] L. Xiao, et al., Biomimetic cytomembrane nanovaccines prevent breast cancer
therapeutic microparticulate oral cancer vaccine, Vaccine 37 (41) (2019) development in the long term, Nanoscale 13 (6) (2021) 3594–3601.
6085–6092. [327] H. Chen, et al., Surface modification of PLGA nanoparticles with biotinylated chitosan
[312] A.C. Hollinshead, et al., Soluble membrane antigens of human malignant for the sustained in vitro release and the enhanced cytotoxicity of epirubicin, Colloids
melanoma cells, Cancer 34 (4) (1974) 1235–1243. Surf. B Biointerfaces 138 (2016) 1–9.
[313] B. Liu, et al., Equipping cancer cell membrane vesicles with functional DNA as a [328] T.T. Liao, M.H. Yang, Hybrid epithelial/mesenchymal state in cancer metastasis:
targeted vaccine for cancer immunotherapy, Nano Lett. 21 (22) (2021) clinical significance and regulatory mechanisms, Cells 9 (3) (2020).
9410–9418. [329] B. Li, et al., The potential of biomimetic nanoparticles for tumor-targeted drug
[314] E.N. Bozeman, et al., Therapeutic efficacy of PD-L1 blockade in a breast cancer delivery, Nanomedicine 13 (16) (2018) 2099–2118.
model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored [330] J.H. Han, et al., Anti-melanogenic effects of oyster hydrolysate in UVB-irradiated
IL-12, Hum. Vaccine Immunother. 12 (2) (2016) 421–430. C57BL/6J mice and B16F10 melanoma cells via downregulation of cAMP
[315] C.D. Pack, et al., Tumor membrane-based vaccine immunotherapy in combination signaling pathway, J. Ethnopharmacol. 229 (2019) 137–144.
with anti-CTLA-4 antibody confers protection against immune checkpoint [331] D. Wang, et al., Erythrocyte-cancer hybrid membrane camouflaged hollow copper
resistant murine triple-negative breast cancer, Hum. Vaccin Immunother. 16 (12) sulfide nanoparticles for prolonged circulation life and homotypic-targeting
(2020) 3184–3193. photothermal/chemotherapy of melanoma, ACS Nano 12 (6) (2018) 5241–5252.
[316] V. Agrahari, et al., Extracellular microvesicles as new industrial therapeutic [332] M. Azharuddin, et al., Nano toolbox in immune modulation and nanovaccines,
frontiers, Trends Biotechnol. 37 (7) (2019) 707–729. Trends Biotechnol. 40 (10) (2022) 1195–1212.
[317] H.Y. Kim, et al., Immunomodulatory lipocomplex functionalized with [333] R. Lu, et al., Inflammation-related cytokines in oral lichen planus: an overview,
photosensitizer-embedded cancer cell membrane inhibits tumor growth and J. Oral. Pathol. Med 44 (1) (2015) 1–14.
metastasis, Nano Lett. 19 (8) (2019) 5185–5193. [334] R.J. Mumper, Z. Cui, Genetic immunization by jet injection of targeted pDNA-
[318] Z. Luo, et al., Self-adjuvanted molecular activator (SeaMac) nanovaccines coated nanoparticles, Methods 31 (3) (2003) 255–262.
promote cancer immunotherapy, Adv. Health Mater. 10 (7) (2021), e2002080. [335] H. Shen, et al., Age and CD161 expression contribute to inter-individual variation
[319] X.S. Xu, et al., Active genetic neutralizing elements for halting or deleting gene in interleukin-23 response in CD8+ memory human T cells, PLoS One 8 (3)
drives, Mol. Cell 80 (2) (2020) 246–262, e4. (2013), e57746.
[320] C. Zhang, et al., Nucleation and growth of polyaniline nanofibers onto liquid [336] E.C. Wamhoff, et al., A specific, glycomimetic langerin ligand for human
metal nanoparticles, Chem. Mater. 32 (11) (2020) 4808–4819. langerhans cell targeting, ACS Cent. Sci. 5 (5) (2019) 808–820.
[321] H.M. Zhang, et al., Effect of TiO₂ nanoparticles on the structure and activity of [337] M. Li, et al., Chemotaxis-driven delivery of nano-pathogenoids for complete
catalase. Chem. Biol. Inter. 219 (2014) 168–174. eradication of tumors post-phototherapy, Nat. Commun. 11 (1) (2020) 1126.
[322] P.A. Savage, D.S. Leventhal, S. Malchow, Shaping the repertoire of tumor- [338] J. Jia, et al., Interactions between nanoparticles and dendritic cells: from the
infiltrating effector and regulatory T cells, Immunol. Rev. 259 (1) (2014) perspective of cancer immunotherapy, Front. Oncol. 8 (2018) 404.
245–258. [339] M. Zaric, et al., Dissolving microneedle delivery of nanoparticle-encapsulated
[323] E. Tasciotti, et al., Mesoporous silicon particles as a multistage delivery system for antigen elicits efficient cross-priming and Th1 immune responses by murine
imaging and therapeutic applications, Nat. Nanotechnol. 3 (3) (2008) 151–157. Langerhans cells, J. Investig. Dermatol. 135 (2) (2015) 425–434.
[324] C. Huang, et al., Glutathione-depleting nanoplatelets for enhanced sonodynamic [340] G. Ueda, et al., Tailored design of protein nanoparticle scaffolds for multivalent
cancer therapy, Nanoscale 13 (8) (2021) 4512–4518. presentation of viral glycoprotein antigens, Elife 9 (2020).
[325] A.V. Kroll, et al., Nanoparticulate delivery of cancer cell membrane elicits
multiantigenic antitumor immunity, Adv. Mater. 29 (47) (2017).

21