Recent advances in nanocarrier-based vaccines for enhanced immunotherapy

 Corresponding author: Meenakshi M Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Recent advances in nanocarrier-based vaccines for enhanced immunotherapy Meenakshi Masilamani *, Prema Ramasamy, Prabhakaran Muruganandan and Sankar Chelladurai Department of Pharmaceutics, KMCH College of Pharmacy, Kovai Estate, Kalappatti Road, India., Postal code:641048 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 Publication history: Received on 17 June 2025; revised on 24 July 2025; accepted on 26 July 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.27.1.2773 Abstract Nanocarrier vaccines represent a groundbreaking advancement in cancer immunotherapy, leveraging nanotechnology to enhance vaccine efficacy and specificity. This review examines the latest advancements in nanocarrier-based cancer vaccine formulations, focusing on the types of nanocarriers utilized and the critical role of their physicochemical properties in influencing immune responses. Key nanocarriers include liposomes, polymeric nanoparticles, lipid nanoparticles, self-assembled protein nanoparticles, inorganic nanoparticles, and virus-like particles. These nanocarriers improve antigen stability, protect against degradation, enable controlled release, and enhance uptake by antigenpresenting cells, resulting in stronger and more durable immune responses. The physicochemical characteristics of nanocarriers, including dimensions, form, surface charge, hydrophobicity, and degradability significantly influence vaccine efficacy by affecting cellular uptake, lymphatic trafficking, antigen presentation, and immune activation. Recent advancements optimize nanocarrier formulations to enhance antigen retention, immune interactions, and tumour modulation. Integrating immune-stimulatory agents like toll-like receptor agonists and cytokines, boosts immunogenicity, overcoming immune tolerance and improving outcomes. The emergence of new patents in nanocarrierbased cancer vaccines highlights innovative approaches in antigen stabilization, adjuvant selection, and targeted delivery. These patented technologies are driving the next generation of cancer immunotherapies, offering promising strategies for achieving precise, effective, and personalized cancer treatment. By synthesizing the latest findings, this review acts as a crucial reference for researchers and clinicians committed to progressing cancer nano vaccine innovation and understanding the emergence of new patents. Keywords: Adjuvants; Cancer immunotherapy; Interactions; Nanocarriers; Patents; Physiochemical properties; Vaccines 1. Introduction In recent years, vaccines have emerged as a vital tool in the fight against infectious diseases. Their exceptional therapeutic and prophylactic efficacy has a significant attention; particularly in the face of emerging intractable diseases.1 The present review article discusses the latest developments on cancer nano vaccines as follows: The three types of vaccines are categorized as follows: •Live attenuated vaccine, which includes bacteria or viruses but is less pathogenic than the naturally occurring pathogen; •Inactivated vaccine, which offers pathogens that have been made inactive by heat or chemical treatment; and •Subunit vaccine that is made from the pathogen's components and regarded as safer than both live attenuated and inactivated vaccines. Subunit vaccination does, however, have many drawbacks, including low effectiveness and insufficient immune response. In contrast, live attenuated vaccines are constrained by the World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2452 possibility of increased post-immunization morbidity and virulence recovery due to insufficient inactivation of bacteria or viruses. Even though a lot of novel vaccinations have been created recently.2 Vaccines activate the immune system's adaptive response, enabling it to recognize and eliminate foreign substances. The vaccine's potency is directly tied to the intensity of this immune response. By boosting the adaptive immune system, vaccines help the body remember and defend against specific pathogens.3 The adaptive immune response is initiated in lymph nodes by lymphocytes, including CD4+ helper T cells, CD8+ T cells, and B cells, which reside alongside antigen-presenting cells (APCs) such as macrophages, dendritic cells (DCs), and follicular dendritic cells. APCs trigger the immune response through specialized antigen uptake mechanisms, allowing T and B lymphocytes to recognize and respond to vaccinations and foreign antigens. Follicular dendritic cells maintain long-lasting immunity by capturing circulating antigen-antibody complexes and retaining them within lymph nodes.4 Vaccines work by triggering the immune system to fight foreign pathogens. For vaccines to be effective, they must be delivered efficiently to immune-related organs, ensuring optimal availability and retention. This requires advanced delivery strategies using specialized platforms. These platforms enable targeted delivery to the immune system and controlled release of vaccine agents, minimizing immune-related side effects like hypersensitivity.5 However, conventional free vaccine administration often suffers from low targeting efficiency and systemic side effects. To overcome this challenge, various innovative vaccine delivery systems have been developed, including liposomes, polymers, cells, inorganic materials, DNA, peptides/proteins, and virus-based systems. These advanced systems significantly enhance antigen delivery to lymph nodes, improving targeting accuracy, delivery efficiency, and biosafety. Furthermore, the administration routes for these systems can be tailored to specific diseases, antigens, and delivery platforms, offering greater flexibility and optimization of vaccine efficacy.6, 7 2. Cancer immunotherapy Cancer is a category of diseases distinguished by uncontrolled cell proliferation as well as the invasion and spread of cells from their point of origin, or primary site, to other parts of the body.8 In general, there are four distinct immunotherapeutic techniques. These include immune checkpoint inhibition, cytokine treatment, cellular therapy, and therapeutic vaccinations.9 Tumour cells use immune-regulatory mechanisms to prevent immune responses and suppress them within the tumour microenvironment.10 Several immune-related cells contribute to the formation of an immunosuppressive microenvironment, including regulatory T cells, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and regulatory B cells. Cancer cells and immune cells in the tumour’s microenvironment produce inhibitory cytokines and checkpoint inhibitors, reducing the effectiveness of anti-tumour T cells.11 Immune Checkpoint Inhibitors (ICIs) perform by disrupting immunological checkpoints, which regulate selftolerance and prevent excessive immune responses.9 The most frequently targeted immune cell checkpoints for cancer immunotherapy include cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3), and lymphocyte activation gene 3 (LAG-3). Six medications, encompassing one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab), and three PD-L1 blockers (atezolizumab, avelumab, and durvalumab) have been approved for the treatment of various cancer types, including hematological tumours like classic Hodgkin's lymphoma as well as solid tumours like melanoma, lung cancer, head and neck cancer, bladder cancer, and Merkel cell cancer.12 Inhibitors of CTLA4, including ipilimumab, act by binding directly to the corresponding checkpoint proteins and preventing them from interacting with their ligands on cancerous cells. A disruption in signaling allows T cells to identify and eliminate cancer cells with more specificity, thus "releasing the brakes" on the immune system.12, 13 Adoptive T cell transfer (ACT) is a new type of transfusion medicine in which lymphocytes are infused to produce anticancer, antiviral, or anti-inflammatory effects. From a promising form of immuno-oncology in preclinical models to the recent commercial licensure of chimeric antigen receptor (CAR) T cells for the treatment of lymphoma and leukemia, the area has moved quite quickly.14 Conversely, ACT involves isolating T cells from a patient and enhancing their anti-tumour activity by ex vivo modification. Recently, chimeric antigen receptors (CAR) have been used to improve T cell specificity by incorporating B and T cell receptor domains.15 In order to trigger a robust immune response against tumours, cancer vaccines, a significant area of immunotherapy, transfer tumour antigens to antigen-presenting cells (APCs). This could have both curative and preventive effects with World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2453 long-term anti-cancer advantages. However, challenges with antigen selection, immunogenicity, lymph node (LN) targeting ability, lysosomal escape capacity, immunological evasion, etc. may be the reason for the inadequate results of their clinical application. To overcome these obstacles, several preclinical and clinical studies show promising outcomes for cancer vaccines based on nanomaterials, with a notable increase in vaccine efficacy.16 For many years, the development of cancer vaccines has made use of nanotechnology including RNA and DNA vaccines, increase the delivery of tumour antigens, which leads to targeted immune responses. Cancer vaccines personalized approach represents the era of precision medicine, in addition to their benefits over earlier therapies. Advancements in vaccine technology, including RNA and DNA vaccines, increase the delivery of tumour antigens, which leads to targeted immune responses.17 Immunotherapy has been a focus of study in cancer treatment in recent years, with notable successes including CAR-T and ICB. Cancer vaccines are a significant area of immunotherapy that safely and effectively stimulate the immune system to produce an anticancer immune response. Moreover, adjuvant therapy with cancer vaccines is employed in conjunction with other immunotherapies to enhance the effectiveness of treatment.16 Figure 1 Cancer immunotherapy types include the use of immune-checkpoint inhibitors, cancer vaccines, cytokines, viruses, and adoptive cell transfer 101 3. Nanocarriers In order to get around the drawbacks of chemotherapy, scientists are creating novel drug delivery methods based on nanotechnology that will enable oncotherapy to advance significantly by delivering anticancer drugs to specific locations at higher concentrations. The use of nanocarriers as a novel cancer therapy tool has reduced many of the drawbacks associated with traditional drug delivery methods. Researchers have tested the potential of using nanotechnology-based drug carriers for cancer management, which has led to the possibility of using nano-drug carriers (10–100 nm) as unique cancer therapy treatments. Different nano-drug carriers have far greater potential applications and efficacies than conventional ones for anticancer drugs.18, 19 Compared to traditional drug delivery methods, nanocarriers have a number of advantages, including longer plasma half-lives, better biodistribution, and targeted drug delivery to tumour microenvironments via endothelial layers.20Researchers have investigated nanocarriers as a versatile tool for delivering drugs and bioactive molecules.21 Different types of nanostructures, including nanoparticles, nanocomposites, nanotubes, and nanofibers, are effective in the identification and management of a wide range of illnesses. These nanostructures are also used as transporting or carrier molecules for medications, vaccines, DNA, proteins, and enzymes.22 One of the distinct characteristics of nanocarriers is their improved pharmacokinetics and biodistribution. • Increased stability, • Increased solubility, • A decrease in toxicity, • Prolonged and Targeted delivery.22 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2454 A. LIPOSOMES B. EMULSIONS Figure 2 Structure of nanocarriers for vaccine antigen delivery 102 Recent trends in nanocarrier vaccines have shown promising potential in revolutionizing cancer immunotherapy. Nanoparticles have emerged as efficacious antigen carriers and immune cell activators, enhancing vaccine efficacy through targeted delivery and modulation of immune responses. Advances in modifying physicochemical properties enable nanoparticles to selectively target specific cells, optimizing anti-cancer activity. Furthermore, innovative nano-based vaccine platforms are being explored, offering alternative administration routes such as oral, nasal, and transdermal delivery. These cutting-edge developments hold significant promise for improving vaccine efficacy, overcoming traditional delivery limitations, and advancing personalized cancer therapy.23 The present review article discusses the latest developments on cancer nano vaccines as follows: 4. Liposomes Traditional liposomes, which range in diameter from 20 nm to a few micrometer’s, have demonstrated exceptional promise in the delivery of vaccines because of their capacity to load hydrophilic and lipophilic components with accessibility and their biodegradability. Liposomes offer modified physicochemical features, controlled antigen release, and chemical changes for targeting. The physicochemical parameters of the antigen, such as its partition coefficient and polarity, as well as the liposome manufacturing techniques all affect the antigen loading efficiency. Conventional liposomes, however, have stability problems such as leakage, bilayer breakage, and early antigen release. Saturated lipids, freeze-drying, cryoprotectants, and sterically stabilized liposomes via polymer complexation or PEG grafting are among recent methods to get beyond these restrictions. Liposomes continue to be a widely used nanocarrier for vaccine delivery in spite of these difficulties.24 4.1. Formulations The cationic lipoplex has been formulated by dissolving 4.46 µmol of DOTAP, cholesterol, and DSPE-PEG2000 in a chloroform: methanol (9:1, v/v) combination. A thin lipid film was the end product of nitrogen digestion and rotary evaporation used to eliminate the organic solvent. After 20 minutes at 60°C and 10 mM Tris-HCl buffer (pH 7.4), this film was rehydrated to produce a cationic liposome solution with a final concentration of 1.45 mg/mL. After that, the mRNA solution and the cationic liposome solution were combined at a weight ratio of 10:1:1 (liposome: protamine: mRNA), respectively, in the presence of protamine. For twenty minutes, this mixture was incubated at room temperature to allow a stable lipoplex complex to develop. The resultant lipoplex was made up of cationic liposomes that contained mRNA and were stabilized by PEGylation and protamine. It was appropriate for use in mRNA delivery applications.25 Using a Zetasizer ZS9 equipment (Malvern Paralytical Ltd.), transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to assess the physical properties of the LPC/mRNA vaccine and DOTAP liposome/mRNA complexes. Protamine sulphate was added to the mRNA solution in 10 mM Tris-HCl buffer at a weight-to-weight ratio of 1:1 in order to produce the complexes. This was followed by a 20-minute incubation period at room temperature. This process promoted mRNA condensation and stability. Subsequently, the LPC or DOTAP liposomes were combined with the protamine-mRNA complex, generating the respective lipoplex complexes. Then, using DLS, the particle size and zeta potential of these complexes were evaluated, offering information about their surface charge, potential interactions with biological membranes, and physical stability.25 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2455 4.2. Polymer based nano vaccines Polymer-based particles are effective vaccination platforms and adjuvants due to their capacity to minimize antigen degradation and clearance, while also enhancing uptake by professional antigen-presenting cells (APCs). Polymer-based systems provide numerous benefits, including versatility and flexibility in design, the ability to incorporate immunomodulators/antigens, mimic infection in various ways, and act as a depot for adaptive immune responses. The major mechanisms are conjugation, encapsulation, adsorption, or simple mixing.26 Figure 3 Interaction of nanoparticles with an antigen of interest. Formulation of nanoparticle and antigen of interest can be implemented through attachment (e.g., conjugation, encapsulation, or adsorption) or simple mixing).103 Stimulus-responsive nanomaterials enhance therapeutic effects and reduce drug-related cytotoxicity by selectively delivering encapsulated medicines to the target place. The encapsulated medications have been released from the nanomaterials using a variety of external energy sources, including temperature, light, magnetic fields, ultrasonic induction, etc. When delivering the medications to the site of injury, internal stimulus responsive carriers make use of the metabolic distinctions that naturally exist between healthy and malignant cells. Several enzymes have been utilized as triggers to release the contents from the proper carriers because they are over expressed in malignant cells.27 Figure 4 Schematic representation of nanovesicles incorporating MMP-9 substrate lipopeptides and reductionsensitive POPE-SS-PEG which render the nanovesicles responsive to extracellular, elevated levels of MMP-9 & GSH.104 Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are overexpressed in various tumours and play a key role in cancer invasion and metastasis, making them valuable targets for enzyme-responsive drug delivery systems. Nanoparticles designed with enzyme-responsive peptides on their surfaces can exploit these enzymes for targeted drug release, but stability in the dynamic physiological environment is critical until they reach the tumour site. Coating nanoparticles with poly (ethylene glycol) (PEG), a process known as PEGylation, enhances their stability by reducing interactions with circulating proteins, lowering interfacial tension, and preventing protein adsorption. This PEG layer facilitates nanoparticle accumulation at the tumour site via the enhanced permeation and retention (EPR) effect. World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2456 However, for effective drug release and therapeutic action at the tumour site, the PEG coating must be removed to activate the carrier's desired functions.28 Matrix metalloproteinase (MMP) levels, particularly MMP-9, are often elevated in the extracellular matrix of various cancers, including pancreatic cancer. In this study, we synthesized an MMP-9-cleavable collagen-mimetic lipopeptide that forms nanosized vesicles when combined with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesteryl-hemi succinate, and a reduction-sensitive PEGylated lipid, 1-palmitoyl-2-oleoyl-sn-glycero-3phosphoethanolamine (POPE-SS-PEG5000). The PEG5000 in POPE-SS-PEG5000 provides long-circulating properties to the nanovesicles, while in the tumour’s extracellular matrix, the high glutathione levels are expected to reduce the POPESS-PEG5000 polymer, shedding the PEG chains. This de-PEGylation exposes the MMP-9-responsive collagen-mimetic lipopeptides to enzymatic hydrolysis, destabilizing the nanovesicles and triggering the release of the encapsulated drugs at the tumour site.29, 30 4.3. Preparation of carboxyfluorescein encapsulated nanovesicles The preparation of carboxyfluorescein-encapsulated nanovesicles, involved the molar ratios of 60:30:5:5 for POPC lipid, synthesized lipopeptide LP, POPE-SS-PEG5000, and cholesteryl hemi succinate. To create a thin lipid layer in a flask with a circular bottom, all of the lipids were dissolved in chloroform and then removed using a rotating evaporator. After vacuum-drying the film for a full night in a desiccator, it was hydrated for two hours at 60°C using a 100 mM carboxyfluorescein solution in HEPES buffer (pH 7.4). The resultant vesicles were extruded through 0.8 μm and 0.2 μm filters to obtain uniform size after being ultrasonicated for 45 minutes with an Aqua sonic bath sonicator (model 250D, power level 9). The vesicles were run down a Sephadex G50 size-exclusion column to remove unencapsulated dye, and the orange band of vesicles encapsulated in carboxyfluorescein was collected for subsequent release and imaging studies. The encapsulation % was not estimated because there was an excess of carboxyfluorescein utilized. 4.4. Preparation of gemcitabine-encapsulated nanovesicles The pH gradient approach was used to create nanovesicles encapsulated with gemcitabine. Chloroform was used to dissolve the lipid-containing nanovesicles, which included POPC, LP, POPE-SSPEG, cholesteryl hemi succinate, and Lissa mine rhodamine lipid (in molar ratios of 59:30:5:5:1). After the chloroform was evaporated at lower pressure, the lipid film that was left over was vacuum-dried. This film was hydrated using a 20 mM citric acid buffer (pH 4), then it was extruded through a 0.2 μm filter and ultrasonically treated for 45 minutes at power level 9. Then, after going through a Sephadex G50 gel-filtration column, the nanovesicles were collected. During chromatography, lipid containing Lissa mine and rhodamine was added to provide colour for the vesicles to be seen. Using a 10:1 lipid-to-drug ratio, these eluted nanovesicles (pH 7.4) were incubated for two hours at 60°C with a 1 mg/mL gemcitabine solution. To extract unencapsulated gemcitabine, the drug-loaded nanovesicles were once more run down the Sephadex G50 column. The nanovesicles, whose entrapment efficiency was estimated to be 50%, were employed in cytotoxicity investigations.31, 32 The hydrodynamic diameters of the vesicles were measured using dynamic light scattering (DLS) (Malvern Zetasizer Nano-ZS90) at a 90° scattering angle in polystyrene cuvettes, with an equilibration time of 120 s and six readings averaged per sample. To study size changes, nanovesicles encapsulating gemcitabine were incubated with MMP-9 and GSH, and size variations were monitored over 24 hours using DLS. Morphological changes were analyzed using atomic force microscopy (AFM), where the vesicles were deposited on a mica sheet and imaged in tapping mode using a Multimode AFM with a Nano scope IIIa controller and J-type piezo scanner (Veeco Metrology Group) equipped with an antimony-doped silicon tip.31 4.5. Inorganic nanoparticles Recently, cancer therapy research has increasingly focused on inorganic nanoparticles (INPs), drawing significant attention from scientists due to their unique physicochemical properties, which are influenced by their material composition and size.33,34 Inorganic nanoparticles (INPs) offer distinct advantages over organic counterparts, showcasing exceptional photosensitivity, superior conductivity, impressive optical properties, magnetic capabilities, and efficient thermal performance. Inorganic nanoparticles are derived from a range of materials, including metal oxides (e.g., iron, manganese, zinc), metals (e.g., gold, silver), carbons (e.g., carbon dots, carbon nanotubes), and semiconductors (e.g., quantum dots). These nanoparticles are widely studied as therapeutic tools for treating various cancers. Prominent examples include mesoporous silica nanoparticles (MSNs), cerium oxide nanoparticles (CeONPs), quantum dots (QDs), carbon nanotubes (CNTs), gold nanoparticles (AuNPs), iron oxide nanoparticles (Fe3O4NPs), silver nanoparticles (AgNPs), and zinc oxide nanoparticles (ZnONPs). These unique traits enable INPs to serve a dual purpose, acting as World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2457 effective carriers for drug delivery while simultaneously functioning as therapeutic agents to enhance cancer treatment outcomes.35, 36 Inorganic nanoparticles (INPs) stand out due to their simple synthesis, extensive surface area, and robust mechanical and chemical stability. Commonly derived from metals, metal oxides, and non-metallic materials like carbon and silica, these nanoparticles provide numerous benefits as drug carriers. Their advantages include enhanced quantum yield, superior drug-loading capacity, and the versatility to facilitate photothermal therapy (PTT) and photodynamic therapy (PDT), making them invaluable in cancer treatment. Inorganic nanoparticles (INPs) present remarkable benefits in cancer therapy, particularly through photothermal therapy (PTT) and photodynamic therapy (PDT). In PTT, INPs generate localized heat, while in PDT, they produce reactive oxygen species, enhancing treatment precision and minimizing harm to healthy tissues. Their high absorption coefficients, stability, and extended circulation time significantly boost therapeutic effectiveness. Moreover, surface modification enables INPs to function as efficient drug delivery systems, offering controlled drug release alongside multifunctional capabilities for bioimaging and therapy. These unique attributes position INPs as highly promising tools for advancing cancer treatments with improved efficacy and targeted action.37 4.6. Photothermal therapy (PTT) Hyperthermia-based cancer therapies involve raising the temperature of targeted tissue to induce cancer cell death (thermal ablation, typically above 45°C) or to increase cancer cell sensitivity to other treatments (mild hyperthermia, with temperatures between 40 and 45°C).38 In photothermal therapy (PTT), NIR-II wavelengths (1000–1700 nm) offer better tissue penetration and improved safety compared to NIR-I (750–900 nm), due to lower scattering and absorption by biological tissues. As a result, NIRII is more efficient for targeting deeper tumours while minimizing damage to surrounding healthy tissue.39 Conventional hyperthermia methods generally raise the temperature of the target tissue through external techniques, including regional hyperthermia, superficial hyperthermia, and whole-body hyperthermia, which use thermal baths, microwaves, or radiofrequency.40 However, this approach often creates a temperature gradient, with the highest temperatures occurring at the body surface and decreasing further from the external heat source. As a result, healthy tissues may also experience elevated temperatures, causing potential unwanted side effects.41 To address these limitations, researchers have focused on developing more efficient techniques, particularly those that can induce localized temperature increases at the tumour site. Nanoparticles (NPs) capable of generating heat in response to external stimuli have emerged as promising solutions, offering a targeted approach that overcomes the drawbacks of conventional hyperthermia methods.42 4.7. Photodynamic therapy (PDT) Photodynamic therapy (PDT) is a non-invasive, painless treatment for various cancers and non-cancerous diseases, targeting cancer cells with high selectivity. It involves a photosensitizer (PS), light to activate the PS, and molecular oxygen from the tumour. When activated, the PS produces reactive oxygen species (ROS) that destroy tumour cells. The ideal wavelength for PDT is between 600–850 nm, known as the "phototherapeutic window. “First-generation (Hematoporphyrin derivative (HpD) and photofrin) PSs have harsh side effects, while second-generation (aminolaevulinic acid (ALA), esterified derivatives of ALA and phthalocyanine compounds) PSs offer reduced toxicity and improved ROS generation. Additionally, when second-generation photosensitizers (PSs) are conjugated with biological carriers, such as nanoparticles, they are classified as third-generation PSs. These "carrier" conjugates enable the PSs to selectively accumulate in cancer cells, enhancing their therapeutic effectiveness.43 4.8. Mechanism of PDT Photodynamic therapy (PDT) involves two main mechanisms in tumour cells with molecular oxygen. Upon light irradiation, the photosensitizer (PS) transitions from a ground state to a single excited state, then to a triplet state. In the type I mechanism, the triplet PS interacts with biomolecules, generating reactive oxygen species (ROS) like hydrogen peroxide. In the type II mechanism, energy is transferred to oxygen, producing singlet oxygen. Both ROS and singlet oxygen cause tumour cell death through apoptosis, necrosis, or autophagy, depending on PS localization.44, 45 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2458 Among these, extra-large pore mesoporous silica nanoparticles (XL-MSNs) have shown significant potential as a prophylactic cancer vaccine. These nanoparticles are engineered to deliver both cancer antigens and danger signals directly to host DCs within the draining lymph nodes, thereby enhancing their ability to elicit robust immune responses. The use of XL-MSNs represents a transformative strategy in cancer immunotherapy, addressing the limitations of traditional DC-based vaccines and offering a scalable, efficient, and minimally invasive method for cancer prevention and treatment. 4.9. Synthesis and characterization of XL-MSNS: Extra-large pore mesoporous silica nanoparticles (XL-MSNs) were prepared by mixing 500 μL of Fe3O4 nanocrystals (6 mg/mL, 6 nm diameter), which were created by heating an iron-oleate complex, into 10 mL of an aqueous solution containing 0.055 M CTAB. The mixture was then vigorously stirred for 30 minutes. The mixture was mixed with a solution comprising 95 mL of DI water, 5 mL of methanol, 3 mL of ammonium hydroxide, and 20 mL of ethyl acetate after being heated to 60°C for 15 minutes. The mixture was then agitated for an additional 500 μL of TEOS and left overnight. The resultant MSNs were placed in 40 mL of ethanol and cleaned three times using ethanol. For three hours at 60°C, the MSNs were agitated in acidic ethanol containing HCl in order to extract the CTAB template and remove the Fe3O4 nanocrystal core. The MSNs were then preserved in 30 mL of ethanol for use in upcoming studies after being cleaned three more times with ethanol. The BET technique was used to analyze the MSNs' pore size and volume. 4.10. Amine modification and ritc conjugation of MSN After adding APTMS to the MSN solution at a TEOS: APTMS molar ratio of 10:1, the reaction was allowed to continue for the entire night. The particles were then washed three times with ethanol. The amine-modified MSNs that resulted were then utilized to manufacture MSN vaccines. RITC-labeled MSNs were created by reacting RITC and APTMS at a 1:10 molar ratio in 750 μL of anhydrous ethanol (99.9%) for a full day in the dark. This resulted in the formation of RITCAPTMS, which allowed MSNs to be tracked in vivo. Then, TEOS and this RITC-APTMS were combined to create RITClabeled MSNs (RITC-MSN). 5. Vaccine formulations A solution of OVA (at a final concentration of 5 mg OVA/mL) was combined with 1 mg of amine-modified MSN in PBS to create the MSN vaccine. The mixture was then spun for two hours and PBS rinsed three times. In order to determine the OVA loading using UV-vis absorbance at 280 nm, the PBS supernatant was collected. After 30 minutes of mixing a CpGODN solution in 500 μL of PBS with the OVA-loaded MSNs, three washings were performed. In order to calculate loading, the UV-vis absorbance at 263 nm was measured using the CpG-ODN supernatant. To prepare the MSR vaccine, 5 mg of MSRs were gently shaken at room temperature for 4 hours with 1 μg of GM-CSF, 100 μg of OVA, and 10 μg of CpG-ODNs. Lyophilization and storage at -20°C were then performed. Prior to vaccination, a 17G needle was used to subcutaneously inject the MSR vaccine into the mouse's flank, resuspended in 200 μL of PBS. The MSR-MSN vaccine was created by combining 5 mg of MSRs with 1 μg of GM-CSF for 4 hours, lyophilizing the mixture, and storing it at -20°C. Prior to vaccination, the GM-CSF-loaded MSRs and 200 μL of the MSN vaccine were mixed to create the MSR-MSN vaccine, which was injected subcutaneously into the mouse flank using a 17G needle. The use of mesoporous silica nanoparticles with extra-large pores (XL-MSNs) has demonstrated remarkable potential in cancer vaccine development, particularly in fostering long-term immunity against tumor recurrence. One of the key findings from recent studies is the significant inhibition of tumor growth in vaccinated, tumor-free mice that were rechallenged with tumors. This robust preventive effect was strongly associated with an elevated presence of memory T cells, which play a critical role in the immune system’s ability to recognize and respond swiftly to recurring tumor antigens. The ability of XL-MSNs to stimulate and sustain such durable immune responses highlights their effectiveness as a cancer vaccine platform. These nanoparticles, designed to deliver cancer antigens and danger signals to dendritic cells in the draining lymph nodes, not only initiate strong antitumor immune responses but also establish long-lasting immunological memory. Consequently, XL-MSNs represent an innovative and promising approach for cancer immunotherapy, offering a scalable and efficient strategy to prevent tumor recurrence and improve patient outcomes.46 6. Self-assembled protein nanoparticles In the past decade, we have developed a technology that enables precise control over the ability of peptides and proteins to self-assemble into nanoparticles with well-defined sizes and shapes. This breakthrough approach allows us to design nanoparticles that are both mechanically and chemically stable. By leveraging expertise in structural biology, biophysics, and computational protein design, we have created a novel method to design epitope strings that self- World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2459 assemble into self-assembling protein nanoparticles (SAPNs). This innovation opens new possibilities for applications in drug delivery, vaccine development, and cancer therapy, where the controlled assembly of protein nanoparticles is crucial for optimizing therapeutic efficacy and targeting. First presented in Raman et al., this technology involves a protein chain composed of two coiled coils connected by a short linker region. The interaction between the coiled coils forces the monomers to self-assemble into spherical nanoparticles. These peptide nanoparticles resemble virus capsids, combining the strong immunogenicity of live attenuated vaccines with the purity and specificity of peptide-based vaccines. SAPNs offer several advantages, including no infection risk compared to live vaccines, and greater versatility and flexibility in design than virus-like particles. Additionally, their ease of expression, purification, and self-assembly significantly reduces production costs and time, making them ideal for large-scale vaccine development.47 Peptide-derived self-assembled molecules hold significant potential as drug nanocarriers, with their diverse structures offering unique advantages in various nanomedicine applications. Several self-assembled proteins and peptides, including albumin, ferritin, and virus-like particles (VLPs), have demonstrated promising roles in cancer therapy. These nanocarriers can be tailored to enhance drug delivery, targeting, and controlled release, making them valuable tools for improving cancer treatment outcomes. Their versatility in design enables optimization for specific therapeutic needs, offering a range of possibilities for advancing cancer therapies. 6.1. Albumin Albumin is the most abundant protein in plasma, with various forms such as ovalbumin (OVA), human serum albumin (HSA), bovine serum albumin (BSA), and rat serum albumin (RSA) isolated for use. Due to its biodegradability, nontoxicity, and immunogenicity, along with the ability to conjugate drugs to its amino acid residues, albumin is a promising nanocarrier for drug delivery. Several albumin-based therapies have been FDA-approved. Additionally, albumin receptors (e.g., Gp18, Gp30, Gp60, and SPARC) are overexpressed on cancer cells, allowing albumin carriers to target tumours. Albumin-based hydrogels (CABH) are also being developed for controlled drug release in acidic environments.48, 49 6.2. Ferritin Ferritin is composed of 24 subunits of heavy and light chains that self-assemble into a symmetric nanocage, measuring 12 nm in size with an internal diameter of 8 nm. The ratio of heavy to light chains can vary, being species and tissuespecific. Ferritin binds to transferrin receptor 1 (TFR1) via the heavy chain, facilitating cellular uptake. TFR1 is low in normal cells but overexpressed in cancers like breast and lung cancer, making ferritin vehicles tumour-selective without additional targeting ligands. Additionally, ferritin's properties, including thermal stability, pH resilience, monodispersed, and biodegradability, make it an ideal drug nanocarrier. Engineered ferritin can also be modified to improve targeting, enhancing safety and precision in cancer therapy.50, 51,52 6.3. Virus like particles Virus-like particles (VLPs) are intricate, self-assembling protein structures composed of multiple subunits that closely resemble the morphology and architecture of native viruses or bacteriophages. However, they are devoid of viral genetic material, making them noninfectious and incapable of replication. Essentially, VLPs are hollow protein shells that mimic the structure of a virus without posing an infection risk. They can be categorized as either enveloped or non-enveloped, depending on whether a lipid envelope is present.53 VLPs are nanoparticles formed through the spontaneous self-assembly of viral structural proteins. Lacking the genetic material required for viral replication, VLPs provide a safe platform, eliminating the risk of unintended viral gene delivery. They serve as versatile tools for presenting various classes of epitopes on their surface, making them particularly valuable for vaccine development. Their capacity to engage dendritic cells (DCs) and stimulate robust B cell responses, along with specific CD4 and CD8 T-cell responses, significantly enhances the effectiveness of vaccines.54 The production of virus-like particles (VLPs) involves several critical steps: choosing a suitable expression system, genetically engineering the host cell or organism, expressing the target proteins, and then purifying and assembling the VLPs.55 Common expression systems for virus-like particle (VLP) production include bacterial systems (e.g., Escherichia coli), yeast systems (e.g., Pichia pastoris), insect cells (e.g., Drosophila melanogaster S2 cells), mammalian cells (e.g., human embryonic kidney [HEK] cells), and plant cells. Each of these systems exhibits unique characteristics that influence both the production yield a critical consideration given the substantial quantities required for vaccine development and the immunogenic properties of the resulting VLPs.56 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2466 25 Tumour vaccine as well as preparation method and application thereof. Immunologic adjuvant. CN115645518A 26 Tetanus vaccine platform for embedding covid19 vaccine. Detoxified recombinant Tetanus Neurotoxin (DrTeNT). US2023201332A1 27 Dendritic cell-mesenchymal stem cell vaccine as well as preparation method and application thereof. 1V209-Chol-Liposome. CN116898958A 28 Nano-carrier for inhibiting tumour dryness as well as preparation method and application of nano-carrier. Fused exosome. CN115990270A 29 Polypeptide vaccine delivery carrier and preparation method thereof. Phenylalanine-based polyester amide polymer. CN116603068A 30 A drug nanocarrier system to deliver a combination of Toll-Like Receptors (TLRs) agonists and/or a Lipoxin plus immunogenic cell death inducing chemotherapeutic agents for cancer immunotherapy. Silicasomes and Liposomes. WO2023172300A1 31 Nanotechnology based intranasal vaccine for covid-19 comprising chitosan. Chitosan. WO2023159082A2 32 Nucleic acid nano vaccine derived from bacterial outer membrane vesicle and use thereof. Bacterial Outer Membrane Vesicles (OMVs). WO2023142999A1 33 Cancer immunotherapy using virus particles. Virus-like particle. US11260121B2 34 Formulated and/or co-formulated compositions containing A2aR antagonist prodrugs useful in the treatment of cancer and methods thereof. LNPs (Lipid Nanoparticles) and SLNPs (Solid Lipid Nanoparticles). US2022401451A1 35 Tumour neoantigen DNA nano vaccine capable of riding red blood cells as well as preparation method and application of tumour neoantigen DNA nano vaccine. PLGA (poly (lactic-coglycolic acid). CN114558127A 36 Use of parasites and extracellular vesicles obtained from parasites in cancer treatment. Extracellular vesicles (exosomes). CN114072167A 37 Methods and compositions for treating cancers. Xenogeneic embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) with Valproic acid (VPA). US11458194B2 38 Bladder cancer targeted nano-drug and preparation method thereof. Amino-modified mesoporous silicon carrier. CN115089728A 39 Nano-enabled immunotherapy in cancer. Lipid-bilayer (LB)-coated nanoparticle. CA3157508A1 40 Tumour vaccine based on dendrimer coated copper sulphide nanoparticles and preparation and application thereof. Dendrimer-coated copper sulphide nanoparticle. CN115300638A 41 Lipid nano-carrier loaded with anti-cancer drug as well as preparation method and application of lipid nanocarrier. Lipid nano-carrier, specifically a solid lipid nanoparticle (SLNP). CN114848594A 42 Self-assembled nanoparticle containing gB protein of EB virus, and preparation method therefor and use thereof. Self-assembled nanoparticle. WO2022120908A1 43 Dual-scale porous silica particle-based composition for preventing or treating cancer. Dual-scale porous Silica particle. KR20210045910A 44 Cationic liposomes for cancer immunotherapy. Cationic Liposomes. US10881612B2 World Journal of Advanced Research and Reviews, 2025, 27(01), 2451-2472 2467 45 Formulated and/or co-formulated liposome compositions containing Indoleamine 2,3-dioxygenase (IDO) antagonist prodrugs useful in the treatment of cancer and methods thereof. Liposomes US2021163418A1 46 BCG (bacillus Calmette Guerin) vaccine complex combined with nano drug carrier and preparation method of BCG vaccine complex. Nano particles coated with a polylactic acid-glycolic acid (PLGA) copolymer. CN112451679A 47 Remote modulation of bicontinuous nanospheres for controlled delivery applications Bicontinuous Nanospheres. US2021308065A1 48 Preparation method of nano vaccine with pH and reduction dual sensitivity and obtained product PEI-modified mesoporous silica nanospheres. CN112315941A 49 Preparation method and application of novel nano quasicell personalized tumour vaccine Hyaluronic acid-based carrier. CN113413463A 50 Golgi apparatus and genetic engineering exosome hybrid membrane coated retinoic acid in-situ spray hydrogel vaccine, and preparation method and application thereof Golgi-exosome hybrid membrane. CN113058031A 51 Poly (ethylene glycol)-block-poly (propylene sulfide) nanocarrier platform for enhanced efficacy of immunosuppressive agents Poly (ethylene glycol)- block-poly (propylene sulfide). US2020383917A1 52 Tumour vaccine combining exosome with immune checkpoint blocker and preparation method thereof Exosome. CN111840528A 53 Novel double-targeted nano drug of customized T-cell epitope vaccine, and preparation method and application thereof. Nano drug that incorporates pMHC polymers (peptidemajor histocompatibility complex polymers) and pancreatic-specific antibodies. CN111135310A 11. Conclusion Nanocarriers represent a versatile and innovative approach to vaccine formulation, offering improved delivery, stability, and efficacy for a wide range of vaccines. This review underscores the potential of nanocarrier-based vaccines as a transformative tool in modern immunization strategies, paving the way for advancements in both preventive and therapeutic applications. By addressing current challenges and exploring emerging trends, nanocarrier vaccines hold promise as a groundbreaking platform to combat infectious diseases, cancer, and other global health concerns. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. 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