Ovarian Cancer Nanovaccines: Recent Strategic Advances from Antigen Selection to Carrier Design

Abstract

Ovarian cancer is one of the most lethal gynecological malignancies. Its immunosuppressive tumor microenvironment and peritoneal dissemination characteristics have severely limited the efficacy of existing immunotherapies. To overcome the poor immunogenicity of tumor antigens and the need for coordinated delivery of antigen and adjuvant, nanovaccines have emerged as a promising strategy. By co-delivering tumor antigens and immunologic adjuvants to antigen-presenting cells, nanovaccines can elicit specific antitumor immune responses. Recently, mRNA-2416, an mRNA-LNP vaccine encoding OX40L, completed a Phase I/II trial in patients with ovarian cancer, providing initial proof-of-concept for intratumoral administration of mRNA-based immunotherapy. This review summarizes antigen design strategies for ovarian cancer nanovaccines and compares the design principles and application progress of major carrier nanoplatforms including liposomes, polymers, inorganic nanoparticles, cell membrane-biomimetic systems, and novel smart responsive nanoplatforms. It further analyzes the core bottlenecks currently facing clinical translation and proposes potential future directions, with the aim of providing a reference for the rational design and clinical translation of ovarian cancer nanovaccines.

Introduction

Ovarian cancer (OC) is one of the most serious malignant tumors threatening women’s health. According to the GLOBOCAN 2022 global cancer statistics, OC accounts for approximately 3.4% of all female cancer cases and 4.8% of cancer-related deaths in women, with an estimated 324,000 new diagnoses and 207,000 deaths globally in 2022.^1,2 In developed countries, OC is the sixth most common cancer and the fifth leading cause of cancer death in women.³ Although the incidence has declined in developed countries, it is rising in Eastern Europe and parts of Asia.⁴ The prognosis of OC is poor, with a 5-year survival rate of about 49% for epithelial OC, although it exceeds 90% for early-stage patients.⁵ As early symptoms are often nonspecific, most patients are diagnosed at stage III or IV.⁶ The current standard treatment for OC remains cytoreductive surgery combined with platinum-based chemotherapy. Although most patients achieve clinical remission after initial treatment, about 70% eventually relapse.^7,8 Chemotherapy resistance further complicates and shortens both progression-free and overall survival.^9,10 This harsh reality highlights the urgent need for novel therapeutic strategies to improve the long-term outcomes in OC patients.

Immunotherapy has emerged as a promising strategy for OC treatment. However, the clinical efficacy of immune checkpoint inhibitors (ICIs) in OC has not met expectations.^11,12 Epithelial OC is relatively insensitive to ICIs, largely due to insufficient immune cell infiltration in the tumor microenvironment (TME) and the dominant presence of immunosuppressive components such as tumor-associated macrophages.¹³ PD-1/PD-L1 blockade has shown limited efficacy in OC as monotherapy or in combination. OC remains one of the few malignancies that respond poorly to ICIs.¹⁴ The reasons for this challenge are multifaceted. First, the OC immune microenvironment is characterized by immunosuppressive cell infiltration, an inhibitory cytokine network, and defective antigen presentation.¹⁵ In addition, tumor heterogeneity and microenvironment-related intrinsic or acquired resistance further impair the efficacy of immunotherapy.^16,17 Therefore, effectively activating antitumor immune responses in OC patients remains a critical challenge.

Nanovaccines provide a novel technical platform to overcome these bottlenecks. They use nanoscale carrier materials to efficiently co-deliver tumor antigens and immune adjuvants to immune cells. This enhances antigen presentation efficiency and activates specific antitumor immune responses.^18,19 Compared with traditional vaccines, nanovaccines offer significant advantages, such as optimal nanoscale size, high stability, sufficient antigen loading capacity, high immunogenicity, tunable antigen presentation, and enhanced retention in lymph nodes (LNs).²⁰ Multifunctional nanoparticles can precisely target tumor sites, improve the delivery efficiency of tumor antigens and immune adjuvants, and reshape the immunosuppressive TME, thereby enhancing the anti-tumor immune response.²¹ Recently, nanovaccines have achieved remarkable progress in tumor therapy.²² For instance, mRNA-4157 (V940), as an individualized neoantigen therapy, can target up to 34 patient-specific tumor neoantigens to induce T cell responses.²³ A randomized Phase IIb clinical trial combining mRNA-4157 with pembrolizumab in resected high-risk melanoma patients has yielded positive results.²⁴ These advances demonstrate the feasibility of nanovaccine technology in cancer immunotherapy and support its application in OC treatment.

This review summarizes the research progress and technical challenges of nanovaccines in OC therapy. We first outline the unique characteristics of the OC immune microenvironment and then discuss antigen selection and design strategies, the technical features of various nanovaccine platforms, and their current applications in OC. We further provide an in-depth analysis of the core bottlenecks facing clinical translation. Through this synthesis, we hope to provide valuable references for future research in the field of OC nanovaccines.

The OC Immune Microenvironment and its Constraints on Vaccine Efficacy

Immunosuppressive Characteristics of the OC Microenvironment

The OC immune microenvironment is characterized by profound immunosuppression, which constitutes a core obstacle to the efficacy of immunotherapy.^25,26 Among the various histological subtypes of OC, high-grade serous OC is the most common and most aggressive form. This subtype shows particularly limited responses to ICIs.^27,28 This insensitivity is closely associated with insufficient infiltration of effector immune cells in the TME and with active immunosuppression dominated by tumor-promoting immune cell populations.^29,30 OC can actively remodel its microenvironment through multiple mechanisms, thereby creating conditions that favor tumor growth and immune evasion.

Hypoxia is a key feature of the OC microenvironment and serves as a critical initiating factor that drives the formation of the immunosuppressive network.^25,31 Under hypoxic conditions, diverse immune cell types in the TME are recruited and reprogrammed toward immunosuppressive phenotypes.²⁵ Tumor-associated macrophages (TAMs) are the most abundant immune cell population in this network and tend to polarize toward an M2-like phenotype under hypoxic stimulation. M2-like TAMs directly inhibit the antitumor activity of effector T cells by secreting immunosuppressive cytokines such as interleukin 10 (IL-10) and transforming growth factor β (TGFβ).^32,33 Simultaneously, TAMs further expand the immunosuppressive network by recruiting regulatory T cells (Tregs) and myeloid derived suppressor cells.²⁹ Tregs extensively infiltrate and become activated in the ovarian TME, where they suppress CD8⁺ T cell proliferation and function, thus constituting a major barrier to immunotherapy.^34,35 Myeloid derived suppressor cells (MDSCs) cooperate in this process by secreting arginase and reactive oxygen species, which impair T cell metabolism and cytotoxic capacity.³⁶ Under the sustained influence of myeloid derived suppressor cells and Tregs, CD8⁺ T cells gradually enter a state of exhaustion. In turn, exhausted CD8⁺ T cells actively promote further macrophage polarization toward the M2 phenotype through secretion of the chemokine CCL3, thereby amplifying immunosuppression.³⁷ Consequently, M2-like TAMs, Tregs, myeloid derived suppressor cells, and exhausted CD8⁺ T cells form a self-reinforcing closed-loop network that continuously sustains immune evasion in OC.

On the basis of this cellular immunosuppressive network, soluble factor mediated signaling pathways constitute the molecular driving force that maintains the operation of the network.³⁸ Multiple immunosuppressive cytokines, including TGFβ, IL-10, and interleukin 6 (IL-6), are markedly overexpressed in the OC microenvironment.^38,39 These cytokines drive immunosuppression through synergistic actions. Specifically, TGFβ activates cancer associated fibroblasts and remodels the extracellular matrix, thereby spatially excluding CD8⁺ T cells from the tumor parenchyma.⁴⁰ IL-10 and IL-6 further limit antitumor immune responses by inhibiting dendritic cell (DC) maturation and directly attenuating T cell function.²⁶ In addition, metabolic reprogramming of OC cells provides sustained energy and metabolic support for immunosuppression. Glycolytic reprogramming leads to lactate accumulation and microenvironmental acidification, which not only directly suppresses effector T cell proliferation and cytotoxic function but also reinforces immunosuppression by influencing the polarization direction of TAMs.⁴¹ The long-term effects of these soluble factors and metabolic alterations ultimately produce structural defects in antigen presentation. Approximately 60% of ovarian tumors exhibit downregulation of major histocompatibility complex class I molecule expression.⁴² This defect allows tumor cells to evade CD8⁺ T cell immune surveillance and represents a key mechanism underlying immunotherapy failure.⁴³ In summary, the OC immune microenvironment employs multiple layered mechanisms including cytokine driven T cell exclusion and functional suppression, metabolic reprogramming that reinforces immune suppression, and major histocompatibility complex (MHC) class I downregulation that blocks antigen recognition. Together, these mechanisms lead to insufficient T cell infiltration and functional exhaustion, which prevent ICIs from achieving the expected therapeutic efficacy.^25,29

Therapeutic Limitations of Conventional Vaccines in OC

Tumor vaccines aim to activate the patient’ s own immune system to recognize and eliminate tumor cells, and they represent an important direction in OC immunotherapy.^44,45 Based on the source of antigens, OC vaccines can be divided into two major categories: predefined antigen vaccines and whole tumor antigen vaccines.⁴⁶ In terms of delivery, DC vaccines serve as an important cellular delivery platform shared by both categories, through which autologous DCs loaded with antigens are reinfused into the body to activate tumor-specific T cell responses.^47,48

Research on predefined antigen vaccines has made some progress in OC, but their clinical translation still faces many challenges. Tumor cells are recognized by the immune system through unique tumor-specific antigens, also called neoantigens, making it critical to include such antigens in vaccines.⁴⁹ However, due to the high heterogeneity and complexity of tumor cells, most neoantigens are patient-specific.⁵⁰ The production of neoantigen based vaccines requires the identification and determination of antigens before vaccine manufacturing, which involves tumor sample sequencing, computational prediction, and peptide synthesis. These steps are complicated and time-consuming.⁵¹ A Phase II trial conducted by the Gynecologic Oncology Group evaluated two p53 peptide vaccine regimens in OC patients at high risk of recurrence. The results showed that only a minority of patients generated detectable p53specific T cell responses, suggesting that the immunogenicity of a single antigen is limited.⁵² More recently, a Phase II TEDOVA trial of the neoantigen epitope based vaccine OSE2101 demonstrated that OSE2101 combined with pembrolizumab maintenance therapy significantly improved progression free survival compared with best supportive care in patients with platinum sensitive recurrent OC, with a hazard ratio of 0.53 (P < 0.001).⁵³ In addition, the folate receptor alpha targeting vaccine TPIV200, when combined with PDL1 antibodies, has been shown to enhance immune responses and overcome resistance mechanisms.⁵⁴ Novel platforms such as the survivin targeted vaccine OVM200 and MaveropepimutS are currently being evaluated in clinical trials.⁵⁵

DC vaccines, as a cellular delivery platform, have received particular attention in OC immunotherapy.⁴⁸ A Phase I/II randomized trial in patients with advanced high‑grade ovarian serous carcinoma compared the immunogenicity of DC vaccines loaded with personalized peptides versus those loaded with tumor lysate. Both preparations induced immune responses, but the personalized peptide‑loaded vaccine showed higher efficiency in inducing CD8⁺ T cell responses.⁵⁶ Another Phase I clinical study reported that tumor‑pulsed DC vaccines could expand neoantigen recognition in OC, suggesting that this strategy has potential in personalized treatment.⁵⁷

Whole tumor antigen (WTA) vaccines represent another important direction, as they utilize whole tumor cells or cell lysates to cover a broad spectrum of antigens without the need for prior antigen identification.⁴⁶ Considering that predefined antigen vaccines are limited in clinical efficacy owing to a lack of broadly expressed tumor antigens, the use of tumor cells or tumor tissues, either autologous or allogeneic, for vaccine preparation could enable polyclonal personalized immunotherapy without the need for neoantigen prediction.⁵⁸ Whole tumor cell vaccines can be prepared in several forms including intact tumor cells, tumor cell lysates, and partial tumor components.⁴⁶ Among these, autologous tumor cells modified ex vivo and reinfused represent an important application. For example, the Vigil vaccine, which is derived from autologous tumor cells modified to express GMCSF and inhibit furin, has shown progression free survival benefit in PDL1 positive patients with recurrent OC when combined with durvalumab in a Phase I/II study.⁵⁹ Silicified tumor cell vaccines represent another emerging whole tumor antigen strategy. This approach uses cryogenic silicification to coat tumor cells with a nanoscale silica layer and then functionalizes the silicified surface with pathogen associated molecular patterns to mimic pathogens.⁶⁰ A silicified whole tumor cell vaccine based on biomineralization technology has been shown in OC mouse models to induce potent antigen-specific T cell immunity and effectively control tumor growth. Moreover, after dehydration, the formulation can be stored at room temperature without loss of efficacy, which supports its potential for personalized vaccine preparation.⁶¹ Although vaccines are relatively safe, their overall clinical efficacy remains limited. A systematic review and meta-analysis encompassing 13 OC studies reported an objective response rate of only 4% in patients with advanced or recurrent OC.⁴⁴

Despite demonstrating some immunogenicity and safety in early-phase clinical studies, the clinical efficacy of the above vaccine strategies still falls far short of expectations.^44,62 This predicament arises from multiple factors. First, antigen delivery and LN targeting are inefficient.⁶³ Tumor vaccines must undergo a cascade of steps including antigen generation and loading, antigen drainage to LNs, uptake by DCs, DC maturation, and antigen cross-presentation to activate T cells.⁶⁴ However, free antigens in conventional vaccines are rapidly cleared or degraded in vivo, making it difficult for them to efficiently reach draining LNs and be effectively taken up by DCs.⁶⁵ Second, the immunosuppressive microenvironment severely restricts the function of vaccine induced T cells.^29,32 The abundant M2-like TAMs, Tregs, and myeloid derived suppressor cells in the OC microenvironment suppress DC maturation and effector T cell activation and proliferation through the secretion of inhibitory cytokines and direct cell-to-cell contact.^35,66 Even if a vaccine successfully induces tumor-specific T cells, these T cells still face functional exhaustion after entering the TME.⁶⁷ Additionally, low expression of major histocompatibility complex class I molecules enables tumor cells to evade CD8⁺ T cell recognition, further undermining the actual effectiveness of vaccine induced immune responses.^43,68 Finally, as OC primarily disseminates through peritoneal spread, the special physiological environment of the peritoneal cavity and the immunosuppressive factors present in ascites further impair the local efficacy of vaccines.⁶⁹ The large number of immunosuppressive cells and soluble factors in the peritoneal cavity constitute a barrier that is difficult for vaccine induced effector T cells to cross.⁷⁰

In summary, the highly immunosuppressive microenvironment of OC, together with the inherent limitations of conventional vaccines in antigen delivery, LN targeting, and peritoneal metastasis escape, severely restricts the efficacy of conventional vaccines in this disease. To overcome these bottlenecks, there is an urgent need to develop novel vaccine strategies that can efficiently deliver antigens and immune adjuvants, precisely target lymphoid tissues, and effectively remodel the immune microenvironment.

Antigen Design and Adjuvant Co-Delivery Strategies for Nanovaccines

The rational selection and design of antigens is the initial step in nanovaccine development. This step directly determines whether the vaccine can effectively activate tumor-specific immune responses. An ideal antigen should possess tumor specificity or tumor-associated characteristics. It should maximize the activation of anti-tumor immunity while minimizing the risk of autoimmunity.⁷¹ However, the low tumor mutational burden in OC makes it difficult to identify mutation-based tumor-specific antigens.^72,73 Therefore, antigen strategies for nanovaccines must balance antigen immunogenicity, tumor specificity, and manufacturing feasibility. Based on the source and properties of antigens, nanovaccine strategies can be divided into three major categories: tumor-associated antigens (TAAs), WTAs and personalized neoantigens.⁷⁴ Beyond antigen selection, the co-delivery of immunologic adjuvants and antigens via nanocarriers (Figure 1) can further enhance the activation of antigen-presenting cells (APCs) and the strength of immune responses.²⁰ This chapter describes the design principles of these three antigen strategies and the synergistic advantages of antigen-adjuvant co-delivery.

Figure 1.

Antigen strategies and immune activation mechanisms of ovarian cancer nanovaccines. The antigen sources for ovarian cancer nanovaccines are divided into three categories: tumor-associated antigens (TAAs, such as WT1, MUC16, and NY-ESO-1), whole-tumor antigens (WTAs, including tumor lysates or cell extracts), and personalized neoantigens. Their immunogenicity and tumor specificity increase sequentially from TAAs to neoantigens. These antigens, together with immunologic adjuvants, are loaded into nanocarriers to formulate nanovaccines. The formulated nanovaccines can be administered through two routes, including lymphatic targeted drainage or intraperitoneal injection. Following administration, the nanovaccines are taken up by dendritic cells and undergo antigen cross-presentation via the MHC class I pathway. Through TCR recognition and CD28/B7 costimulatory signaling, the presented antigens activate naive CD8⁺ T cells, which then differentiate into cytotoxic effector CD8⁺ T cells. These effector cells ultimately recognize and kill ovarian cancer cells in a targeted manner. In addition, tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, and the peritoneal metastatic microenvironment collectively constitute multiple biological barriers, which represent the core challenges that must be overcome in nanovaccine design. This figure was originally created with the assistance of Gemini 3 and NanoBanana 2 (AI-assisted illustration). It is an original work that contains no previously published or third-party material, and its scientific accuracy has been verified and confirmed by all authors.

TAAs and Multi-Epitope Design

TAAs are antigen molecules that are highly expressed on tumor cells but are expressed at low levels or not expressed in normal tissues.¹⁹ Multiple TAAs are clearly overexpressed in OC.⁶² These antigens can be classified into several categories according to their biological functions. The first category includes antigens involved in metabolism and proliferation regulation, such as folate receptor alpha (FRα) and human epidermal growth factor receptor 2 (HER2). FRα participates in folate metabolism and cell proliferation. It is overexpressed on the surface of more than 90% of high-grade serous OC cells but is expressed at very low levels in normal tissues.^75,76 HER2 belongs to the growth factor receptor family. It is overexpressed in some OCs and participates in proliferative signaling in tumor cells.^77,78 The second category includes antigens involved in cell adhesion, migration, and immune evasion, including mesothelin (MSLN), mucin 16 (MUC16), and epithelial cell adhesion molecule (EpCAM). MSLN is overexpressed in multiple solid tumors including OC and participates in cell adhesion and metastasis.⁷⁹ MUC16 and its cleaved fragment CA125 belong to the mucin family and are expressed in more than 95% of non-mucinous advanced epithelial OCs.⁸⁰ EpCAM participates in cell-cell adhesion signaling and is also widely overexpressed in OC.⁸¹ The third category includes cancer-testis antigens and other aberrantly expressed antigens, such as NY-ESO-1, WT1, and p53. These antigens are highly restricted in normal tissues but show varying degrees of aberrant expression in OC.^82–85 The differential expression patterns of these antigens are not isolated from one another. They reflect differences in the molecular subtypes and signaling pathway activation profiles of OC. These patterns provide a molecular basis for vaccine design based on single or combined antigens.

Nanovaccine design based on TAAs can be divided into two strategies: single-epitope vaccines and multi-epitope vaccines.⁸⁶ Single-epitope vaccines focus on a single dominant epitope from one antigen. Their design is relatively simple and quality control is straightforward. However, the breadth of immune responses induced by a single epitope is limited. This makes the vaccine vulnerable to immune escape caused by tumor antigen loss or epitope mutation.⁸⁷ Multi-epitope vaccines integrate multiple epitopes from different regions of the same antigen or from multiple different antigens into a single vaccine. This approach aims to broaden the coverage of immune responses and reduce the risk of tumor escape.⁸⁸ Nanocarriers can encapsulate multiple peptide epitopes within the same nanoparticle, enabling the synergistic delivery of different antigens.^89,90 For example, Shariati et al designed a peptide vaccine based on nanoliposomes loaded with multi-epitopes of P53, WT1, and CA125. The peptide loading efficiency reached 96%. This vaccine increased the BAX/BCL2 expression ratio to promote apoptosis and significantly reduced tumor volume in humanized PDX mouse models.⁹¹ The FRα multi-epitope peptide vaccine TPIV200 entered a randomized, double-blind, multicenter phase II clinical trial. The results showed that although TPIV200 had good immunogenicity and acceptable tolerability, it failed to significantly extend progression-free survival.⁹² This indicates that multi-epitope vaccines targeting a single antigen may still require combination with checkpoint inhibitors or other immunomodulatory strategies to achieve better clinical benefit. In addition, Chiaro et al systematically analyzed the immunopeptidome of ovarian tumors using proteogenomic methods. They identified multiple shared peptide vaccine candidates across patient populations.⁹³ Similarly, Bassoy et al identified novel immunogenic TAAs such as TTLL8, POTEE, and PKMYT1. These antigens are expressed at low levels in normal tissues but are upregulated in OC. They provide new candidate targets for antigen selection in OC nanovaccines.⁹⁴

WTAs and Personalized Antigens

Unlike vaccines based on defined TAAs, WTA strategies use whole tumor cells or their lysates as the antigen source. These strategies do not require prior identification of specific antigen targets. They provide a complete tumor antigen profile and can effectively address tumor heterogeneity and immune escape caused by antigen loss.⁴⁶ Autologous tumor cell lysates can be extracted from surgically resected tumor tissues. They contain all of the patient’s neoantigens and represent a promising source of personalized antigens.^95,96 Zhao et al encapsulated tumor cell lysates derived from a mouse OC cell line into liposomes. They then conjugated these liposomes to cowpea mosaic virus as a potent adjuvant to construct the TCL-Lip-CPMV conjugate vaccine. In the ID8-Defb29/VEGF-a-Luc OC mouse model, this vaccine protected mice from tumor challenge by improving antigen processing and presentation and priming adaptive anti-tumor immunity.⁹⁷

Recently, tumor-derived extracellular vesicles (EVs) have attracted considerable attention as WTA carriers.⁹⁸ EVs carry bioactive molecules such as proteins, lipids, and nucleic acids derived from their parent cells. They are naturally enriched with TAAs. They also have nanometer-scale dimensions and good biocompatibility, making them ideal candidate platforms for autologous cancer vaccines.^99,100 A recent study coated tumor-derived EVs with pH-sensitive manganese dioxide using microfluidic technology to construct a self-reporting nanovaccine. The surface mineralization process chemically blocked inhibitory ligands such as CD47 to promote DC uptake. The vesicles degraded under lysosomal conditions to release tumor antigens and Mn²⁺. The released Mn²⁺ further activated the cGAS-STING pathway. This enhanced T1-weighted magnetic resonance imaging contrast and enabled visualization of DC trafficking. In OC models, this nanovaccine effectively inhibited tumor growth and peritoneal dissemination.¹⁰¹

WTA strategies are further evolving toward personalized neoantigen vaccines. Neoantigens are entirely new amino acid sequences generated by gene mutations in tumor cells. They exist only in tumor tissues and are not expressed in normal tissues. Therefore, they have high tumor specificity and immunogenicity.^102,103 Personalized neoantigen vaccines represent an important direction for the development of WTA strategies. However, the low tumor mutational burden in OC makes neoantigen identification challenging.^72,104 Nevertheless, through whole-exome sequencing and bioinformatics analysis, patient-specific neoantigens can be identified from tumor tissues. These neoantigens can then be used to design personalized vaccines.¹⁰⁵ mRNA-2416, a lipid nanoparticle-encapsulated mRNA vaccine encoding OX40L, completed a first-in-human phase I/II clinical trial in patients with advanced solid tumors and OC. In the exploratory OC cohort, the study did not meet the predefined primary efficacy endpoints. However, tumor biopsies showed increased OX40L protein expression, elevated PD-L1, and enhanced pro-inflammatory responses.¹⁰⁶ In addition to mRNA vaccines, peptide vaccines have also made clinical progress in neoantigen delivery. A case report showed that a patient with brain-metastasized OC achieved long-term survival after receiving personalized neoantigen-derived peptide vaccine combined with anti-PD-1 therapy.¹⁰⁷ For clinical scenarios where neoantigen identification is difficult or tumor heterogeneity is high, biomimetic nanovaccines offer an alternative strategy. These vaccines use tumor cell membrane coating to present multiple tumor antigens without prior identification of immunogenic tumor antigens. This provides a new technological approach for personalized immunotherapy.^104,108

Antigen and Adjuvant Co-Delivery Design

Tumor antigens have inherently low immunogenicity. In addition, multiple inhibitory signals exist in the OC microenvironment. These factors make it difficult for antigens alone to effectively activate naive T cells.¹⁰⁹ To overcome this limitation, the incorporation of immunologic adjuvants into vaccine formulations becomes a necessary strategy. Immunologic adjuvants can enhance the immunogenicity of antigens, promote the maturation of APCs, and direct appropriate types of immune responses.¹⁹ More importantly, the co-delivery of antigens and adjuvants via nanocarriers allows both components to reach the same APC simultaneously. This promotes adaptive immune responses.²⁰ This is one of the main features that distinguish nanovaccines from conventional physically mixed vaccines. In addition, nanocarriers can protect antigens and adjuvants from rapid degradation in vivo. They can prolong the retention time of these components in LNs and the tumor microenvironment.¹¹⁰ Nanocarriers can also achieve active targeting to LNs or tumor tissues through surface functionalization. This further increases the local concentration of antigens and adjuvants at the site of action.^111,112

In OC nanovaccine research, the commonly used immunologic adjuvants mainly include toll-like receptor (TLR) agonists and STING pathway agonists.^109,113,114 TLRs are key innate immune receptors that recognize pathogen-associated molecular patterns. Their agonists can effectively promote the activation of DCs and macrophages.¹¹⁵ For example, CpG oligodeoxynucleotides are agonists of TLR9 and can induce Th1-type immune responses.^95,116 Monophosphoryl lipid A (MPLA), a weak agonist of TLR4, has been approved by the FDA as a vaccine adjuvant for human use.¹¹⁷ Zhou et al designed an antigen-capturing nanovaccine by modifying the surface with the tumor-targeting peptide TMTP1 and the DC receptor mannose. The core of this nanovaccine was encapsulated with MPLA adjuvant. After chemotherapy, this nanovaccine captured and enriched tumor-specific antigens, promoted DC maturation, and activated adaptive immunity.¹¹⁸

The STING pathway is a core mechanism of innate immune recognition of cytosolic DNA. Its activation induces the production of type I interferons and promotes DC maturation and T cell cross-priming.¹¹⁹ STING agonists show unique advantages in OC nanovaccines. Zhong et al designed a folate-modified antigen-trapping nanoprobe. They combined exogenous cyclic GMP-AMP with chemotherapy-induced double-stranded DNA to synergistically enhance STING pathway activation. In ovarian tumor models, this approach significantly inhibited tumor growth, metastasis, and recurrence.¹²⁰ Similarly, Fu et al self-assembled a cisplatin polyprodrug containing thioketal units with the STING small-molecule agonist SR-717 to form redox-responsive nanoparticles. This achieved synergistic anti-tumor effects through the combination of chemotherapy and STING pathway activation.¹²¹ In addition to synergy with chemotherapeutic agents, STING agonists can also be combined with immune checkpoint blockade strategies. Notably, the combination of TLR9 and STING agonists effectively induced neoantigen-specific T cell immunity in tumor models and significantly improved the efficacy of immune checkpoint blockade.¹²²

The strategy of antigen and adjuvant co-delivery using nanocarriers has shown promising application prospects in OC therapy. For example, Li et al constructed a LN targeting in situ nanovaccine called CpG@Man-P/Tra/Gel. This system exhibited matrix metalloproteinase-2-sensitive release properties. It released trametinib and CpG nanoadjuvants. When combined with PD-1 blockade, this vaccine effectively inhibited the growth of primary OC.⁶⁴ In addition, Tang et al designed a hybrid lipid-silica nanosystem capable of simultaneously loading model antigens and CpG adjuvants. They established a multi-component immune platform that effectively promoted immune responses in OC mouse models.¹²³ These studies demonstrate that nanocarrier-mediated co-delivery of antigens and adjuvants can enhance immune activation while reducing systemic toxicity. This provides important technical support for the clinical translation of OC nanovaccines.

Nanovaccines for OC Therapy

The technological advantages of nanovaccines originate from the physicochemical properties and biological functions of their carrier materials. Compared with conventional free antigens or physically mixed vaccines, nanocarriers co-deliver antigens and immunologic adjuvants to APCs, protect antigens from enzymatic degradation and clearance, and achieve active accumulation in lymphoid tissues or tumor regions through surface functionalization strategies.^110,111 Based on the differences in carrier materials, the nanovaccine platforms currently used for OC treatment can be broadly divided into five categories: liposomes, polymers, inorganic nanoparticles, cell membrane-biomimetic systems, and novel smart platforms (Figure 2). Each platform has distinct characteristics in material composition, preparation processes, and biological effects. These differences determine their respective application scopes and limitations. This chapter describes the structural design principles of these five nanovaccine platforms and their application progress in OC, and discusses the major bottlenecks currently facing clinical translation.

Figure 2.

Nanovaccine platforms for ovarian cancer. Currently, the mainstream nanovaccine platforms for ovarian cancer include five major categories. (1) Liposomal nanovaccines, the most rapid progress toward clinical translation, primarily enhancing antigen presentation and T cell activation through lymph node enrichment. (2) Polymeric nanovaccines, which rely on PLGA matrices to encapsulate antigens and adjuvants. They possess the potential for in situ vaccine construction, continuously releasing antigens at tumor sites and inducing potent T cell responses. (3) Inorganic nanovaccines, including mesoporous silica nanoparticles and metal-organic frameworks. Some of these materials possess intrinsic immunomodulatory properties and can integrate imaging or therapeutic components to achieve theranostic functions, thereby enhancing vaccine efficacy through synergistic immunostimulation and imaging/therapy integration. (4) Cell membrane-biomimetic nanovaccines, this platform fully preserves the membrane proteins and biological functions of the source cells, offering combined advantages of immune evasion, homologous tumor targeting, and enhanced antigen presentation. They can efficiently deliver antigens and induce potent T cell activation. (5) Novel nanovaccine, including plant virus-like particles, stimuli-responsive carriers, and theranostic nanovaccines. These platforms represent the frontier of precision and personalized nanovaccine development, enabling precise activation and enhancement of immune responses. Given the characteristic peritoneal dissemination of ovarian cancer, nanovaccines can be administered via intraperitoneal local injection. The vaccines can remodel the tumor immune microenvironment by promoting dendritic cell maturation, increasing effector T cell infiltration, reducing myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and upregulating pro-inflammatory cytokines. Ultimately, this induces long-lasting systemic anti-tumor immune memory, achieving sustained killing of tumor cells. This figure was originally created with the assistance of Gemini 3 and NanoBanana 2 (AI-assisted illustration). It is an original work that contains no previously published or third-party material, and its scientific accuracy has been verified and confirmed by all authors.

Liposomal Nanovaccine Platforms

Liposomes are spherical vesicles composed of phospholipid bilayers, with structures similar to cell membranes. They can simultaneously encapsulate hydrophilic antigens in the aqueous core and hydrophobic adjuvants in the lipid bilayer.^124,125 The particle size of liposomes can be precisely controlled within the range of tens to hundreds of nanometers, enabling active lymphatic drainage to LNs for uptake by resident APCs such as DCs.^126–128 Liposome surfaces can be modified with PEG to prolong circulation time, or conjugated with targeting ligands to achieve active targeting of specific cells or tissues.^129,130 In addition, liposomes possess good biocompatibility and low immunogenicity, and they were the first nanoscale drug delivery system successfully translated into clinical practice.^131,132 As derivatives of liposomes, solid lipid nanoparticles and nanostructured lipid carriers also demonstrate great potential in vaccine adjuvant platforms due to their excellent biocompatibility, tunable drug release profiles, and efficient antigen delivery capabilities.¹³³

In the development of vaccines against OC, liposomal platforms are widely used for antigen delivery and in situ vaccine construction. For example, PVNLME, a multi-epitope peptide vaccine based on nanoliposomes loaded with P53, WT1, and CA125. It has a mean particle size of 112 nm and a peptide loading efficiency of 96%, and effectively inhibited tumor growth in PDX humanized mouse models.⁹¹ Zhong et al constructed a folate-modified antigen-trapping liposomal nanoprobe AGO@FA-lip, which induces immunogenic cell death in tumor cells using oxaliplatin (OXA) to release tumor antigens and dsDNA. Combined with exogenous cGAMP, this system synergistically enhances STING pathway activation and significantly inhibits tumor growth, metastasis, and recurrence in OC mouse models.¹²⁰ These studies demonstrate the feasibility of liposomal platforms for multi-epitope antigen co-encapsulation and in situ antigen capture. However, both studies were limited to subcutaneous tumor models, and the efficacy against peritoneal disseminated OC requires further validation. The complex multi-component design may also increase the difficulty of clinical translation. Furthermore, the application of liposomal carriers in OC extends to targeted delivery of cytokines and immunologic adjuvants. Recently, Pires et al developed layer-by-layer self-assembled liposomal nanoparticles with poly-L-arginine/poly-L-glutamate coatings for systemic delivery of IL-12. Following intraperitoneal administration, this platform concentrated IL-12 in disseminated OC tumors. As the coating gradually shed over time, IL-12 was slowly released in the tumor bed. In OC mouse models, this liposomal nanovaccine significantly promoted T cell accumulation, prolonged survival, and sensitized tumors to ICIs.¹³⁴ Similarly, systemically delivered LbL liposomal IL-12 nanoparticles significantly reduced severe toxicity compared with carrier-free IL-12, achieving a 30% complete survival rate.¹³⁵ However, the preparation process of LbL technology is relatively complex, which may limit its scalability for manufacturing.

Polymeric Nanovaccine Platforms

Polymeric nanocarriers represent another important class of vaccine delivery platforms, representative materials include PLGA, PEI, and polyamino acids.^136,137 Among these, PLGA is the most extensively studied. It has good biodegradability and biocompatibility, can be metabolized to water and carbon dioxide for excretion, and has been approved by the FDA for injectable drug delivery systems.^138–140 The particle size, surface charge, and drug release rate of PLGA nanoparticles can be precisely controlled by adjusting the molecular weight of the polymer, the lactic acid/glycolic acid ratio, and the preparation process.^140,141 Based on these tunable structural parameters, PLGA nanoparticles can encapsulate antigens and immunologic adjuvants to regulate immune cell activity and differentiation, thereby enhancing the efficacy of tumor immunotherapy.¹⁴² Notably, PLGA itself possesses antigen-capturing capacity, enabling it to capture antigens released after radiotherapy or chemotherapy. This property confers unique advantages for its application as an in situ vaccine carrier.¹⁴³

Currently, polymeric platforms for OC therapy encompass multiple strategies. NP-TP1@M-M, as a PLGA-based antigen-capturing nanovaccine, its surface is modified with the tumor-targeting peptide TMTP1 and the DC receptor mannose, while the core is loaded with MPLA adjuvant. It can capture and enrich tumor-specific antigens after chemotherapy and activate adaptive immunity.¹¹⁸ Xiong et al encapsulated CpG immunologic adjuvant within PLGA and coated it with ID8 OC cell membranes. The resulting PLGA-CpG@ID8-M nanovaccine mediated reprogramming of TAMs through the Gbp2-Pin1-NFκB signaling pathway and significantly prolonged survival in ID8 tumor-bearing mice.¹¹⁶ Additionally, Kaskow et al developed degradable polycationic nanoparticles based on PBAE. By increasing the hydrophobicity of PBAE and employing a pH-shift-mediated assembly method, they achieved efficient cytosolic delivery of the STINGΔTM protein, which delayed tumor growth and extended survival in syngeneic mouse models of OC.¹⁴⁴ Although polymeric nanocarriers offer flexibility and designability in antigen capture, immunologic adjuvant delivery, and gene/protein drug delivery, the long-term safety of their degradation products and batch-to-batch variability of some polymers remain important factors constraining clinical translation.¹³⁹

Inorganic Nanovaccine Platforms

Inorganic nanoparticles have attracted increasing attention in the tumor vaccine field due to their unique physicochemical properties and immunomodulatory functions.^145,146 Common inorganic nanocarriers include mesoporous silica nanoparticles (MSNs), metal–organic frameworks (MOFs), and nano-aluminum hydroxide.^147,148 MSNs have high specific surface area, tunable pore size, controllable morphology, and excellent biocompatibility. These properties enable efficient loading of antigens and adjuvants.^149,150 Moreover, some inorganic nanomaterials possess intrinsic immunomodulatory functions and can serve as vaccine adjuvants.¹⁵¹ Taking mesoporous silica as an example, these particles can directly regulate immune cell activity through their unique structural properties, rather than acting merely as passive carriers.¹⁵⁰ Furthermore, inorganic nanoparticles can integrate imaging functions, which provides possibilities for the development of theranostic vaccine.¹⁵² However, the non-biodegradable or slowly degrading nature of inorganic nanomaterials may pose potential long-term toxicity risks, which is a critical issue requiring attention in clinical translation.¹⁵³

The application of inorganic nanoplatforms in OC therapy involves multiple material types. Marwedel et al functionalized MSNs with TLR agonists to construct immunogenic mesoporous silica nanoparticles (iMSN). In a mouse model of metastatic OC, intraperitoneally administered iMSN was rapidly taken up by peritoneal myeloid cells and transported to milky spots and FALCs in adipose tissues, thereby reducing suppressive T cells and increasing activated memory T cells. Only two doses of iMSN were sufficient to eliminate or reduce OC and effectively prevent subsequent tumor engraftment. Notably, subcutaneous and intravenous administration of iMSN showed no therapeutic effect in mice with peritoneal metastases, indicating that the intraperitoneal route is critical for activating regional immune cells.¹⁰⁹ In terms of MOF materials, Lin et al developed an epigenetic nanoagonist CMZ-Pt-SA@HA, composed of Mn-ZIF-8 encapsulating CaO₂ and co-loaded with cisplatin and the HDAC inhibitor SAHA. SAHA epigenetically downregulates resistance protein expression, CaO₂ triggers calcium overload and oxygen release, and Mn²⁺/Zn²⁺ enhances oxidative stress and STING signaling, collectively demonstrating significant therapeutic efficacy in platinum-resistant OC models.¹⁵⁴ Another study engineered M1-polarized macrophages to deliver MTO-loaded MOF nanoparticles, achieving triple-modal synergy of chemotherapy, photothermal ablation, and chemodynamic therapy under near-infrared irradiation. Combined with anti-PD-L1 therapy, this approach achieved near-complete eradication of peritoneal metastases in OC mouse models.¹⁵⁵ Although MSN and MOF platforms each have advantages in immune activation and multi-modal synergistic therapy, their long-term biodistribution, safety of degradation products, and in vivo metabolic pathways still lack systematic evaluation.

Cell Membrane-Biomimetic Nanovaccine Platforms

Liposomal, polymeric, and inorganic nanoplatforms all use synthetic materials as their carrier cores, whereas cell membrane-biomimetic nanovaccines represent a fundamentally different design concept.^104,156 This type of platform combines natural cell membranes with synthetic nanoscale cores, using the inherent biological functions of cell membranes to endow nanoparticles with unique biomimetic properties.¹⁵⁷ Compared with synthetic nanocarriers, cell membrane-biomimetic platforms offer significant advantages in immune evasion, targeting capability, and antigen presentation.^158,159 The multiple proteins retained on the cell membrane surface, such as adhesion molecules, receptors, and immunomodulatory molecules, enable nanoparticles to mimic the biological behavior of source cells, including prolonged circulation time, homotypic targeting, and effective interaction with immune cells.^160–162 Moreover, cell membrane-biomimetic nanovaccines can leverage the complex biological functions of natural cell membranes to achieve effects that are difficult to attain with conventional synthetic carriers. For example, tumor cell membrane-coated nanoparticles can inherit the surface antigen profile of source tumor cells, presenting multiple tumor antigens without prior identification of specific immunogenic antigens.¹⁶³ DC membrane-coated nanoparticles inherit antigen presentation and T cell activation capabilities.¹⁶⁴

In terms of fusion cell membrane strategies, Zhang et al fused DCs with OC cells, extracted the fusion cell membrane, and coated it onto PLGA nanoparticles loaded with CpG adjuvant to prepare FCM-NPs nanovaccines. The fusion process promoted DC maturation, upregulated the expression of costimulatory molecules CD80/CD86, and accelerated DC homing to LNs. FCM-NPs possess both the immunogenicity of tumor cells and the antigen-presenting capacity of DCs, and were shown to delay OC growth and inhibit metastasis in subcutaneous xenograft, patient-derived xenograft, and peritoneal metastasis models.¹⁶⁵ Single cell type membrane-coated nanovaccines have also made significant progress. For example, Cheng et al developed a biomimetic nanovaccine derived from DCs called mini DC, which was prepared by cell membrane coating technology and retained the antigen presentation capacity and T cell stimulatory function of DCs. In OC mouse models, mini DC delayed tumor growth and reduced tumor metastasis.¹⁶⁶ Li et al encapsulated a CD40 ligand-encoding oncolytic adenovirus within tumor cell membranes to construct a biomimetic nanovaccine platform. This platform achieved sustained antigen release and localized delivery of costimulatory molecules to tumors. In a peritoneal carcinomatosis model, combination therapy with anti-PD-1 induced complete tumor eradication in 50% of mice.¹⁶⁷ Aobulikasimu et al developed a DC membrane-biomimetic nanovaccine GA-NPs@DCV loaded with galangin (GA). This vaccine utilized GA to induce tumor ICD, providing abundant specific TAAs, and inhibited immune evasion through the Stat3/IDO1/AhR signaling axis while remodeling the TME via regulation of the tryptophan metabolic pathway.¹⁶⁸ However, individual differences in cell membrane sources, complexity of preparation processes, and difficulties in scale-up manufacturing remain key obstacles constraining clinical translation.^156,169

Novel Nanovaccine Platforms

Beyond the four major platform categories described above, novel strategies including plant virus-like nanovaccines, smart responsive nanovaccines, and theranostic nanovaccines have also demonstrated unique potential in OC therapy. Plant virus-like nanovaccines utilize the natural nanostructures of plant viruses as immunostimulatory platforms.¹⁷⁰ CPMV is a 30 nm plant virus nanoparticle with intrinsic immunogenicity that can serve as an in situ vaccine to directly activate innate immune cells.¹⁷¹ Czapar et al developed a sustained-release formulation of CPMV with PAMAM generation 4 dendrimers (CPMV-G4). This formulation formed aggregates based on electrostatic interactions, and the aggregate size and CPMV release could be regulated by salt concentration. In a peritoneal OC mouse model, a single dose of CPMV-G4 achieved comparable efficacy to weekly administration of soluble CPMV.¹⁷² Another study covalently conjugated CPMV with an anti-PD-1 peptide (SNTSESF). The results showed that enhanced efficacy against metastatic OC was only observed when the anti-PD-1 peptide was conjugated to CPMV rather than added as a free peptide.¹⁷³ This is likely attributable to the prolonged tumor retention and favorable intratumoral distribution of the nanoparticle formulation compared with the free peptide. Although the immunogenicity of plant virus-like nanovaccines is an advantage, it may also induce neutralizing antibody responses that affect the efficacy of repeated administration.

Smart responsive nanovaccines and theranostic nanovaccines represent the trend toward precision medicine in nanovaccine development. One study based on a smart nanogel system provided a new approach for LN targeting in situ vaccines. This system utilized an MMP-2-sensitive nanogel as a carrier to specifically release trametinib (Tra) and CpG nanoadjuvants in the TME, and achieved active LN targeting through mannose modification. Combined with PD-1 blockade, this approach not only inhibited primary tumor growth but also induced systemic immune responses against OC recurrence and metastasis.⁶⁴ For theranostic applications, tumor-derived EVs coated with pH-sensitive MnO₂ using microfluidic technology formed a nanoplatform with both immunotherapeutic and MRI functions. This platform enhanced DC uptake efficiency by blocking inhibitory ligands such as CD47, and released Mn²⁺ upon degradation in the lysosomal acidic environment. The released Mn²⁺ both activated the cGAS-STING pathway and served as an MRI contrast agent for real-time visualization of DC trafficking. In OC models, this platform effectively inhibited tumor growth and peritoneal dissemination, and early LN MRI signals correlated with long-term therapeutic responses.¹⁰¹ Although the design concepts of these two platforms each have distinctive features, the in vivo response efficiency and specificity still require further optimization.

Clinical Translation of Nanovaccines

The nanovaccine platforms described above each have distinct characteristics in material composition, design principles, and functional properties (Table 1). These differences determine their respective application ranges and limitations in OC therapy. The liposomal nanovaccine platform is relatively mature for clinical translation,^124,125 with advantages including good biocompatibility, mature preparation processes, flexible surface modification, and multiple liposomal drugs already approved for clinical use.¹⁷⁴ Nevertheless, liposome stability and drug release kinetics remain challenging, and the rapid clearance of some liposomal formulations in vivo limits their delivery efficiency.¹⁷⁵ The polymeric nanovaccine platform, represented by PLGA, possesses intrinsic antigen-capturing capacity, providing unique advantages for in situ vaccine applications.¹⁴³ However, degradation products of polymeric materials may cause local inflammatory responses, and some polymers have complex preparation processes with significant batch-to-batch variability.¹³⁹ Inorganic nanovaccine platforms offer high loading capacity, structural stability, and intrinsic immunomodulatory activity.^149,150 For example, mesoporous silica and MOF materials can simultaneously load multiple functional components to achieve multi-modal synergistic therapy.^154,155 Despite these advantages, the long-term biosafety and in vivo metabolic pathways of inorganic materials require systematic evaluation, and the non-biodegradable nature of some materials may pose potential toxicity risks.¹⁵³ Cell membrane-biomimetic nanovaccine platforms retain the complex biological functions of natural cell membranes, enabling homotypic targeting, immune evasion, and antigen presentation. They represent a frontier direction for the integration of biological and synthetic materials.^104,156 Whereas, the source of cell membranes, standardization of preparation, and scale-up manufacturing present challenges for clinical translation.^156,169 Novel platforms such as plant virus-like nanovaccines, while possessing unique immunostimulatory properties, are still in early stages of clinical research.^172,173

Table 1.

Comparison of Different Nanovaccines for Ovarian Cancer Therapy

Nanovaccine	Mechanism	Current Status	Key Outcomes	Advantages	Clinical Translation Challenges	References
Liposomal nanovaccines	1. Encapsulation of multi-epitope antigens (P53/WT1/CA125) to induce apoptosis; 2. Delivery of IL-12 cytokine to activate T cell immunity; 3. Folate-modified antigen capture combined with STING pathway activation.	mRNA-2416 has completed Phase I/II clinical trials, and the rest are in the animal-level research stage.	1. Reducing tumor volume in animal models; 2. Inhibiting tumor metastasis and recurrence; 3. Prolonging survival period.	1. Multiple liposomal drugs already approved, most clinically mature platform; 2. Own good biocompatibility, flexible surface modification, and can co-encapsulate hydrophilic and hydrophobic drugs.	1. Stability and release kinetics remain challenging; 2. Rapid clearance of some formulation limits delivery efficiency.	[91,120,134,135,174]
Polymeric nanovaccines	1. PLGA captures tumor antigens released after chemotherapy and activates adaptive immunity; 2. Reprograming tumor-associated macrophage s via Gbp2-Pin1-NFκB pathway; 3. Delivering STING protein fragments to activate intracellular STING signaling.	Preclinical (animal models)	1. Activating adaptive immunity; 2. Delaying tumor growth and prolonging survival in tumor-bearing mice.	1. PLGA is biodegradable, and its particle size and release kinetics can be precisely controlled; 2. PLGA possesses antigen-capturing capacity.	1. Long-term safety of degradation products unknown; 2. Batch-to-batch variability for some polymers; 3. Extrapolation from subcutaneous to peritoneal dissemination models is limited.	[118,121,144]
Inorganic nanovaccines	1. Activating peritoneal myeloid cells and be transported to the fat-related lymphoid aggregation areas, thereby reducing the inhibitory T cells; 2. Enabling epigenetic regulation and STING activation; 3. Macrophage-delivered MTO-MOF achieves triple-modal synergy.	Preclinical (animal models)	1. Clearing ovarian cancer and prevented engraftment with two doses; 2. Achieving near-complete eradication of peritoneal metastases.	3. High loading capacity and structural stability; 2. Hold intrinsic immunomodulatory activity; 3. Possess the ability to integrate imaging functions for theranostic applications.	1. Long-term biosafety unknown; non-biodegradable nature poses potential toxicity risks; 2. Lack of systematic evaluation of in vivo metabolic pathways.	[109,154,155]
Cell membrane-biomimetic nanovaccines	1. Fusion cell membrane combines antigen presentation with tumor immunogenicity; 2. DC membrane nanovaccines inherit antigen presentation and T cell stimulatory functions; 3. Enabling sustained antigen release and formation of immunological hotspots; 4. Inhibiting immune evasion via STAT3/IDO1/AhR axis.	Preclinical (animal models)	1. Delaying tumor growth and metastasis; 2. Inducing long-term protective immunity.	1. Retain complex biological functions of natural cell membranes; 2. Enable homotypic targeting, immune evasion, and antigen presentation; 3. Present multiple tumor-associated antigens without prior antigen identification.	1. High individual variability in membrane sources; 2. Difficult to standardize preparation; 3. Scale-up manufacturing extremely challenging.	[116,165–168]
Novel nanovaccine platforms	1. Plant virus acts as in situ vaccine to activate innate immunity; 2. Smart nanogel enables MMP-2-responsive release and active lymph nodus targeting; 3. EV-MnO2 theranostic platform blocks CD47, releases Mn2+ to activate cGAS-STING and enhance MRI.	Preclinical (animal models)	1. Inhibiting primary tumor growth and inducing systemic immunity; 2. Early LN-MRI signals from mTEV correlated with therapeutic responses.	1. Plant viruses possess intrinsic immunogenicity; 2. Smart responsive systems enable spatiotemporally controlled release; 3. Theranostic platforms integrate therapy with real-time monitoring.	1. Plant viruses may induce neutralizing antibodies affecting repeated administration; 2. In vivo response efficiency and specificity require optimization; 3. Complex preparation processes	[64,101,172,173]

Currently, the combination of nanovaccines with ICIs has demonstrated synergistic efficacy in multiple studies. As described above, IL-12 liposomal nanoparticles combined with ICIs enhanced tumor immune responses.¹³⁴ PLGA-CpG@ID8-M nanovaccines combined with chemotherapy achieved synergistic anti-tumor effects through TAM reprogramming.¹¹⁶ CpG@Man-P/Tra/Gel nanovaccines combined with PD-1 blockade effectively inhibited primary tumor growth.⁶⁴ Concurrently, multiple related clinical trials are also ongoing. A lipid nanoparticle-encapsulated mRNA vaccine (mRNA-2416) has completed a first-in-human phase I/II clinical trial in patients with advanced solid tumors and OC (NCT03323398). This study confirmed the proof-of-concept for intratumoral injection of mRNA-based immunotherapy.¹⁰⁶ The oncolytic virus immunotherapy agent Olvi-Vec combined with platinum-doublet chemotherapy and bevacizumab for platinum-resistant/refractory OC is also being evaluated in a Phase III clinical trial (OnPrime, GOG-3076, NCT06131840). This trial is based on the positive objective response rates and PFS data observed in the phase II VIRO-15 study.¹⁷⁶ The advancement of these clinical studies marks the gradual transition of OC nanovaccines from laboratory research toward clinical application.

However, successful translation from preclinical research to clinical application still faces multiple bottlenecks. Insufficient tumor delivery and LN targeting efficiency is a primary obstacle.^126,127 After systemic administration, nanovaccines must overcome multiple barriers including protein corona formation in the blood, capture by the mononuclear phagocyte system, and high tumor interstitial pressure to reach tumor sites or LNs.¹²⁶ Even for nanoparticles with active targeting functions, the actual targeting efficiency in vivo remains far below expectations.¹²⁹ Second, the high heterogeneity of OC makes it difficult for vaccines based on single or few antigens to cover all tumor subclones. Antigen loss or MHC downregulation can lead to tumor tolerance to vaccine-induced immune responses.¹⁷⁷ Even when nanovaccines successfully deliver antigens and adjuvants, the large numbers of immunosuppressive cells and inhibitory cytokines in the TME of OC can still impair effector T cell function.¹³ Furthermore, the preparation of nanovaccines involves complex process steps, making batch-to-batch quality consistency difficult to ensure. For platforms requiring individualized preparation, such as cell membrane-biomimetic and personalized neoantigen vaccines, the challenges of scale-up manufacturing are particularly prominent.¹⁷⁸ In addition, mouse OC models differ substantially from human disease in terms of TME, tumor heterogeneity, and peritoneal dissemination patterns. This means that nanovaccines showing excellent performance in animal models often fail to replicate the same efficacy in clinical trials.¹⁷⁹ In summary, the clinical translation of nanovaccines still requires continued exploration and synergistic breakthroughs across multiple levels, including material design, immunological mechanisms, and clinical research strategies.

Conclusion and Future Prospects

Through the coordinated delivery of antigens and adjuvants, diverse nanovaccine platforms, including liposomes, polymers, inorganic nanoparticles, cell membrane-biomimetic systems, and smart responsive systems have shown considerable promise for overcoming the immunosuppressive microenvironment of ovarian cancer in preclinical and early clinical studies. Their clinical translation, however, remains constrained by insufficient tumor delivery and LN targeting, tumor heterogeneity and antigen escape, and the gap between preclinical models and human disease. Future progress is expected to rely on personalized neoantigen nanovaccines and rational combinations with immune checkpoint inhibitors, supported by more clinically relevant preclinical models, standardized manufacturing and quality control, and rigorous safety evaluation systems.

Funding Statement

This work was supported by Jiaxing Science and Technology Program (2023AY31021, 2024AY40013).

Abbreviations

APC, antigen-presenting cells; CPMV-G4, CPMV with PAMAM generation 4 dendrimers; DC, dendritic cell; EpCAM, epithelial cell adhesion molecule; EVs, extracellular vesicles; FRα, folate receptor alpha; GA, galangin; HER2, human epidermal growth factor receptor 2; ICIs, immune checkpoint inhibitors; IL-6, interleukin 6; IL-10, interleukin 10; iMSN, immunogenic mesoporous silica nanoparticles; LNs, lymph nodes; MDSCs, Myeloid derived suppressor cells; MHC, major histocompatibility complex; MOFs, metal–organic frameworks; MPLA, MPLA; MSLN, mesothelin; MSNs, mesoporous silica nanoparticles; MUC16, mucin 16; OC, Ovarian cancer; OXA, oxaliplatin; TAAs, tumor-associated antigens; TAMs, tumor-associated macrophages; TGFβ, transforming growth factor β; TLR, toll-like receptor; TME, tumor microenvironment; Tregs, regulatory T cells; WTAS, whole-tumor antigens.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflict of interest.