Nanovaccine Platform Research Articles

Oligonucleotide-Linked Lipid Nanoparticles as a Versatile mRNA Nanovaccine Platform.

An effective delivery platform is crucial for the development of mRNA vaccines and therapeutics. Here, a versatile platform utilizing cholesterol-modified oligonucleotides (L-oligo) that bind to the mRNA within lipid nanoparticles (LNP), and enables the effective delivery of the mRNA into target cells is introduced. mRNA incorporated into LNPs via linkage with L-oligo, termed oligonucleotide-linked LNP (lnLNP), is superior in cellular uptake and transfection efficiency in target cells in vitro and in vivo, compared to the conventional LNP formulations. It is further applied lnLNP as an mRNA vaccine platform for SARS-CoV-2, demonstrating robust induction of neutralizing activity as well as polyfunctional SARS-CoV-2-specific T-cell response in vivo. The current strategy can be versatilely applied to different LNP platforms, for vaccine and therapeutic applications against various diseases, such as infections and cancers.

DENV Peptides Delivered as Spherical Nucleic Acid Constructs Enhance Antigen Presentation and Immunogenicity in vitro and in vivo.

The global prevalence of Dengue virus (DENV) infection poses a significant health risk, urging the need for effective vaccinations. Peptide vaccines, known for their capacity to induce comprehensive immunity against multiple virus serotypes, offer promise due to their stability, safety, and design flexibility. Spherical nucleic acid (SNA), particularly those with gold nanoparticle cores, present an attractive avenue for enhancing peptide vaccine efficacy due to their modularity and immunomodulatory properties. The spherical nucleic acid-TBB (SNA-TBB), a novel nanovaccine construct, was fabricated through the co-functionalization process of SNA with epitope peptide, targeting all four serotypes of the DENV. This innovative approach aims to enhance immunogenicity and provide broad-spectrum protection against DENV infections. The physicochemical properties of SNA-TBB were characterized using dynamic light scattering, zeta potential measurement, and transmission electron microscopy. In vitro assessments included endocytosis studies, cytotoxicity evaluation, bone marrow-dendritic cells (BMDCs) maturation and activation analysis, cytokine detection, RNA sequencing, and transcript level analysis in BMDCs. In vivo immunization studies in mice involved evaluating IgG antibody titers, serum protection against DENV infection and safety assessment of nanovaccines. SNA-TBB demonstrated successful synthesis, enhanced endocytosis, and favorable physicochemical properties. In vitro assessments revealed no cytotoxicity and promoted BMDCs maturation. Cytokine analyses exhibited heightened IL-12p70, TNF-α, and IL-1β levels. Transcriptomic analysis highlighted genes linked to BMDCs maturation and immune responses. In vivo studies immunization with SNA-TBB resulted in elevated antigen-specific IgG antibody levels and conferred protection against DENV infection in neonatal mice. Evaluation of in vivo safety showed no signs of adverse effects in vital organs. The study demonstrates the successful development of SNA-TBB as a promising nanovaccine platform against DENV infection and highlights the potential of SNA-based peptide vaccines as a strategy for developing safe and effective antiviral immunotherapy.

Intranasal Multiepitope PD-L1-siRNA-Based Nanovaccine: The Next-Gen COVID-19 Immunotherapy.

The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are nanotechnology-based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next-generation multiepitope nanovaccines co-deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD-L1 expression. As a case study, we focused on SARS-CoV-2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular- and humoral-specific responses against SARS-CoV-2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS-CoV-2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology-based vaccines, it is shown that the lyophilized nanovaccine is stable for long-term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats.

Uniform Polymeric Nanovaccine Platform for Improving the Availability and Efficacy of Neoantigen Peptides.

Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8+ T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.

Robust Systemic and Mucosal Immune Responses to Coxsackievirus B3 Elicited by Spider Silk Protein Based Nanovaccines via Subcutaneous Immunization

AbstractCoxsackievirus B3 (CVB3) is a member of the enterovirus genus and linked to several diseases, including myocarditis, which can progress to dilated cardiomyopathy. Despite ongoing preclinical efforts, no clinically approved vaccines against CVB3 are currently available, highlighting the urgent need for effective prophylactic solutions. In this study, a nanovaccine platform based on spider minor ampullate silk protein (MiSp) is introduced. This platform utilizes protein nanoparticles engineered from chimeric proteins that incorporate CVB3 antigenic peptides into customized MiSp, subsequently loaded with all‐trans retinoic acid (RA). These functional nanovaccines are capable of eliciting both mucosal and systemic immune responses following subcutaneous administration and demonstrate significant protective effects against CVB3 infection in mice. This study signifies an approach in peptide‐based parenteral vaccine strategies, utilizing engineered MiSp nanoparticles combined with RA. This methodology represents a promising pathway for preventing enterovirus infections by leveraging the unique immunomodulatory properties of spidroins and RA to combat these pathogens effectively.

A General Strategy toward Self-assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses.

Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4)to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

A bi-adjuvant nanovaccine amplifying STING activation for cancer immunotherapy

The insufficient immune activation and immunosuppressive microenvironment restrict the therapeutic efficacy of cancer vaccines. Herein, we exploited a bi-adjuvant nanovaccine to amplify the activation of the stimulator of interferon genes (STING) for potent and durable anti-tumor immunity. STING agonist (MnO2 nanoparticles), toll-like receptor 9 agonist (CpG), and antigenic proteins or peptides were strategically formulated into nanovaccines (MnC NVs) by a one-step biomineralization method. The nanovaccine efficiently targeted dendritic cells of draining lymph nodes, in which CpG-mediated the stimulation of nuclear factor-kappa B pathway augmented STING signaling. RNA sequencing analysis validated the enhanced expression of relevant genes of type-I interferon signaling pathways. The priming of antigen-specific CD8+ T cells and humoral immune responses led to potent tumor growth inhibition and prolonged survival time in melanoma and human papilloma virus-derived tumor models. MnC NVs were able to synergize with immune checkpoint blockade therapy, with 80 % survival over 40 days in TC-1 tumor model. Moreover, rechallenging of tumor-free mice with homotypic cells resulted in complete tumor growth inhibition, suggesting the generation of a long-term memory effect. The simplified nanovaccine platform provides a safe and robust strategy to boost STING-mediated anti-tumor immunity for personalized cancer immunotherapy, showing significant potential for clinical translation.

Biomimetic Multilayered Lipid Nanovesicles for Potent Protein Vaccination.

Lipid vesicles are widely used for drug and gene delivery, but their structural instability reduces in vivo efficacy and requires specialized handling. To address these limitations, strategies like lipid cross-linking and polymer-lipid conjugation are suggested to enhance stability and biological efficacy. However, the in vivo metabolism of these altered lipids remains unclear, necessitating further studies. A new stabilization technique without chemical modification is urgently needed. Here, a bio-mimetic approach for fabricating robust multilamellar lipid vesicles to enhance in vivo delivery and stabilization of protein antigens is presented. This method leverages 1-O-acylceramide, a natural skin lipid, to facilitate the self-assembly of lipid nanovesicles. Incorporating 1-O-acylceramide, anchoring lipid bilayers akin to its role in the stratum corneum, provides excellent stability under environmental stresses, including freeze-thaw cycles. Encapsulating ovalbumin as a model antigen and the adjuvant monophosphoryl lipid A demonstrates the vesicle's potential as a nanovaccine platform. In vitro studies show enhanced immune responses with both unilamellar and multilamellar vesicles, but in vivo analyses highlight the superior efficiency of multilamellar vesicles in inducing higher antibody and cytokine levels. This work suggests ceramide-induced multilamellar lipid vesicles as an effective nanovaccine platform for enhanced antigen delivery and stability.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

Polyanhydride nanovaccine against H3N2 influenza A virus generates mucosal resident and systemic immunity promoting protection

Influenza A virus (IAV) causes significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. The antigenic drift/shift of IAV continually gives rise to new strains and subtypes, aiding IAV in circumventing previously established immunity. As a result, there has been substantial interest in developing a broadly protective IAV vaccine that induces, durable immunity against multiple IAVs. Previously, a polyanhydride nanoparticle-based vaccine or nanovaccine (IAV-nanovax) encapsulating H1N1 IAV antigens was reported, which induced pulmonary B and T cell immunity and resulted in cross-strain protection against IAV. A key feature of IAV-nanovax is its ability to easily incorporate diverse proteins/payloads, potentially increasing its ability to provide broad protection against IAV and/or other pathogens. Due to human susceptibility to both H1N1 and H3N2 IAV, several H3N2 nanovaccines were formulated herein with multiple IAV antigens to examine the “plug-and-play” nature of the polyanhydride nanovaccine platform and determine their ability to induce humoral and cellular immunity and broad-based protection similar to IAV-nanovax. The H3N2-based IAV nanovaccine formulations induced systemic and mucosal B cell responses which were associated with antigen-specific antibodies. Additionally, systemic and lung-tissue resident CD4 and CD8 T cell responses were enhanced post-vaccination. These immune responses corresponded with protection against both homologous and heterosubtypic IAV infection. Overall, these results demonstrate the plug-and-play nature of the polyanhydride nanovaccine platform and its ability to generate immunity and protection against IAV utilizing diverse antigenic payloads.

Abstract 5001: Personalized neoantigen/cancer-testis antigen nanovaccine for advanced solid tumors, a single-arm, open-label pilot study

Abstract Background: Neoantigens, derived from somatic mutations in tumor cells, have been identified as promising targets of immunotherapy. A personalized neoantigen/cancer-testis antigen (CTA) nanovaccine (PNVAC) platform has been established by us previously, and demonstrated its feasibility, safety and efficacy in preventing recurrence of high-risk resected gastric/gastroesophageal junction (G/GEJ) cancer in both preclinical and clinical studies. This study aims to explore the universality of PNVAC monotherapy or combined with anti-angiogenesis drugs or anti-programmed death 1 (PD-1) in patients with multiple advanced solid malignancies. Methods: Patient-specific neoantigens were selected based on tumor-specific mutations identified by whole-exome sequencing (WES) and RNA sequencing of paired blood and tumor tissues. Bioinformatic analysis for neoantigen prediction, including sequencing read filtering, human leukocyte antigen (HLA) typing and neoantigen filtering was performed. PNVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens designed to induce specific T cell responses. PNVAC is administrated to patients with metastatic solid tumors on days 1, 4, 8, 15, 22, 43 (prime phase) and 64, 85 and 169 (boost phase) alone, or combined with anti-angiogenesis or anti-PD-1 drugs. Safety, immunogenicity and clinical efficacy are evaluated. Results: Of the 30 enrolled patients, no treatment-related severe adverse events (AEs) occurred and the vast majority of AEs were limited to grade 1-2, only 1 patient developed grade 3 thrombocytopenia. The objective response rate (ORR) was 26.7% (8/30), including 2 cases of complete response (CR) and 6 cases of partial response (PR), and a disease control rate (DCR) of 66.7% achieved. The median progression-free survival (PFS) was 9.90 months (95% CI, 3.46-16.34 months), while the median overall survival (OS) was not reached (range, 0.80-43.53 months), and the estimated 1- and 2-year survival rates were 86.2% and 60.6%. Notably, among the 21 patients who had relapsed disease after previous ICB and/or anti-angiogenesis, disease control was asserted in 14 (66.7%) of them (7 of SD, 5 of PR, 2 of CR). ORR of this set was 33.3% (7/21), higher than that of all the enrolled patients (26.7%), and the set without prior ICB and/or anti-angiogenesis treatment (11.1%). For immune analysis, PNVAC elicited robust and persistent immune responses against neoantigens/CTAs. Additionally, peripheral T cells with a cytotoxic phenotype tended to increase after vaccination, and immune memory was also detected in some representative patients. Conclusions: These data supported the safety, immunogenicity, and efficacy of this regimen in patients with advanced solid malignancies, thus broadening the application and combined strategies of neoantigen-based vaccines. Clinical trial information: ChiCTR1800017319. Citation Format: Jia Wei, Qin Liu, Lijing Zhu, Jie Shao, Ju Yang, Guanghui Xu, Nandie Wu, Hanbing Wang, Rutian Li, Huizi Sha, Qiuping Xu, Jie Shen, Li Xie, Lifeng Wang, Juan Du, Lanqi Cen, Manman Tian, Lixia Yu, Baorui Liu. Personalized neoantigen/cancer-testis antigen nanovaccine for advanced solid tumors, a single-arm, open-label pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5001.

Self-Adjuvanting Polyguanidine Nanovaccines for Cancer Immunotherapy.

Tapping into the innate immune system's power, nanovaccines can induce tumor-specific immune responses, which is a promising strategy in cancer immunotherapy. However, traditional vaccine design, requiring simultaneous loading of antigens and adjuvants, is complex and poses challenges for mass production. Here, we developed a tumor nanovaccine platform that integrates adjuvant functions into the delivery vehicle, using branched polyguanidine (PolyGu) nanovaccines. These nanovaccines were produced by modifying polyethylenimine (PEI) with various guanidine groups, transforming PEI's cytotoxicity into innate immune activation. The PolyGu nanovaccines based on poly(phenyl biguanidine ) (Poly-PBG) effectively stimulated dendritic cells, promoted their maturation via the TLR4 and NLRP3 pathways, and displayed robust in vivo immune activity. They significantly inhibited tumor growth and extended mouse survival. The PolyGu also showed promise for constructing more potent mRNA-based nanovaccines, offering a platform for personalized cancer vaccine. This work advances cancer immunotherapy toward potential clinical application by introducing a paradigm for developing self-adjuvanting nanovaccines.

Biologically Self-Assembled Tumor Cell-Derived Cancer Nanovaccines as an All-in-One Platform for Cancer Immunotherapy.

Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.

RNA Origami Functions as a Self-Adjuvanted Nanovaccine Platform for Cancer Immunotherapy.

Peptide-based vaccines have been widely investigated in cancer immunotherapy. Despite their high specificity, safety, and low production cost, these vaccines have shown limited success in clinical studies, owing to their poor immunogenicity. Extensive efforts have been devoted to increasing the immunogenicity of peptide vaccines by mixing peptides with adjuvants and/or promoting their delivery to tumor-draining lymph nodes (TdLNs) for better antigen presentation by and maturation of dendritic cells. Among these efforts, the exploration of various nanoparticles has been at the forefront of the rational design and construction of peptide-based vaccines. Here, we present a nanovaccine platform that is built on a self-assembled RNA origami (RNA-OG) nanostructure. As previously reported, this RNA-OG nanostructure is a potent toll-like receptor (TLR)3 agonist. In addition, due to its robust synthesis and versatility in modification, RNA-OG could be readily linked to peptides of interest. Thus, these RNA-OG nanostructures function as adjuvanted nanocarriers to construct RNA-OG-peptide nanovaccines that are uniform in size, consistent in peptide loading, and highly stable. Here, we demonstrate that the assembled RNA-OG-peptide nanovaccines induced dendritic cell maturation, reduced tumor-mediated immunosuppression, and mobilized tumor-specific CD8+ T cell responses at the tumor site. Together, these actions led to the elicitation of an effective antitumor immunity that increased the survival of tumor-bearing mice. The combination of RNA-OG-based nanovaccines with the α-PD-1 immune checkpoint blockade further enhanced the immunity. Hence, our RNA-OG nanostructures represent a robust, simple, and highly effective platform to empower peptide-based vaccines for cancer immunotherapy.

Systemic and mucosal immune responses in red tilapia (Oreochromis sp.) following immersion vaccination with a chitosan polymer-based nanovaccine against Aeromonas veronii

A mucoadhesive chitosan polymer-based nanoplatform has been increasingly recognized as an effective mucosal vaccine delivery system for fish. The present study aimed to investigate the effectiveness of immersion vaccination with a chitosan polymer-based nanovaccine to elicit an immune response in serum and mucus of red tilapia and evaluate its protective efficacy after immersion challenge with a heterogenous strain of Aeromonas veronii UDRT09. Six hundred red tilapia (22 ± 1.8 g) were randomly allocated into four experimental groups: control, empty-polymeric nanoparticle (PC), formalin-killed vaccine (FKV), and chitosan polymer-based nanovaccine (CS-NV) in triplicate. The specific IgM antibody levels and their bactericidal activity were assessed in serum and mucus for 28 days after immersion vaccination and followed by immersion challenge with A. veronii. The immersion vaccine was found to be safe for red tilapia, with no mortalities occurring during the vaccination procedure. The specific IgM antibody levels and bactericidal activity against A. veronii in both serum and mucus were significantly higher in red tilapia vaccinated with CS-NV compared to the FKV and control groups at all time points. Furthermore, the serum lysozyme activity, ACH50, and total Ig levels demonstrated a significant elevation in the groups vaccinated with CS-NV compared to the FKV and control groups. Importantly, the Relative Percentage Survival (RPS) value of the CS-NV group (71 %) was significantly higher than that of the FKV (15.12 %) and PC (2.33 %) groups, respectively. This indicates that the chitosan polymer-based nanovaccine platform is an effective delivery system for the immersion vaccination of tilapia.

Establishment of a novel tumor neoantigen prediction tool for personalized vaccine design

ABSTRACT The personalized neoantigen nanovaccine (PNVAC) platform for patients with gastric cancer we established previously exhibited promising anti-tumor immunoreaction. However, limited by the ability of traditional neoantigen prediction tools, a portion of epitopes failed to induce specific immune response. In order to filter out more neoantigens to optimize our PNVAC platform, we develop a novel neoantigen prediction model, NUCC. This prediction tool trained through a deep learning approach exhibits better neoantigen prediction performance than other prediction tools, not only in two independent epitope datasets, but also in a totally new epitope dataset we construct from scratch, including 25 patients with advance gastric cancer and 150 candidate mutant peptides, 13 of which prove to be neoantigen by immunogenicity test in vitro. Our work lay the foundation for the improvement of our PNVAC platform for gastric cancer in the future.

A Universal Cyclodextrin-Based Nanovaccine Platform Delivers Epitope Peptides for Enhanced Antitumor Immunity.

Currently, there is still an intense demand for a simple and scalable delivery platform for peptide-based cancer vaccines. Herein, a cyclodextrin-based polymer nanovaccine platform (CDNP) is designed for the codelivery of peptides with two immune adjuvants [the Toll-like receptor (TLR)7/8 agonist R848 and the TLR9 agonist CpG] that is broadly applicable to epitope peptides with diverse sequences. Specifically, the cyclodextrin-based polymers are covalently linked to epitope peptides via a bioreactive bond-containing cross-linker (PNC-DTDE-PNC) and then physically load with R848 and CpG to obtain CDNP. The CDNP efficiently accumulats in the lymph nodes (LNs), greatly facilitating antigen capture and cross-presentation by antigen-presenting cells. The immunogenicity of the epitope peptides is significantly enhanced by the codelivery and synergy of the adjuvants, and the CDNP shows the ability to inhibit tumor progression in diverse tumor-bearing mouse models. It is concluded that CDNP holds promise as an optimized peptide-based cancer vaccine platform.

Nanovaccines for cancer immunotherapy: Focusing on complex formation between adjuvant and antigen.

As an interesting cancer immunotherapy approach, cancer vaccines have been developed to deliver tumor antigens and adjuvants to antigen-presenting cells (APCs). Although the safety and easy production shifted the vaccine designing platforms toward the subunit vaccines, their efficacy is limited due to inefficient vaccine delivery. Nanotechnology-based vaccines, called nanovaccines, address the delivery limitations through co-delivery of antigens and adjuvants into lymphoid organs and APCs and their intracellular release, leading to cross-presentation of antigens and induction of potent anti-tumor immune responses. Although the nanovaccines, either as encapsulating agents or biomimetic nanoparticles, exert the desired anti-tumor activities, there is evidence that the mixing formulation to form nanocomplexes between antigens and adjuvants based on the electrostatic interactions provokes high levels of immune responses owing to Ags' availability and faster release. Here, we summarized the various platforms for developing cancer vaccines and the advantages of using delivery systems. The cancer nanovaccines, including nanoparticle-based and biomimetic-based nanovaccines, are discussed in detail. Finally, we focused on the nanocomplexes formation between antigens and adjuvants as promising cancer nanovaccine platforms.

Multi-signaling pathway activation by pH responsive manganese particles for enhanced vaccination

As metal ions play important roles in the process of immunomodulation, immunotherapy based on metal ions has attracted tremendous interests in recent years. Here, we screened common metal ions and found that Mn2+ could enhance the immune function in vitro. A new type of nanovaccine is thus fabricated by a biomimetic approach using nanoscale coordination polymer formed by Mn2+ and 2-methylimidazole (2-MI) to encapsulate ovalbumin (OVA) protein, a model antigen, obtaining OVA@MM nanoparticles. Compared to free OVA, OVA@MM nanoparticles could more effectively induce the maturation of bone marrow-derived dendritic cells (BMDCs) and their subsequent antigen cross-presentation. The particles made of Mn2+ and 2-MI could activate immune-regulated signal pathways to enhance the immune functions of BMDCs. Such OVA@MM nanovaccine could not only provide prophylactic effect to inhibit the growth of B16-OVA tumor on immunized mice, but also significantly inhibit tumor growth in the mice with B16-OVA tumor combined with anti-programmed cell death protein 1 (anti-PD-1) antibody. Therefore, this nanovaccine platform based on Mn2+, 2-MI and antigen may provide a simple, effective and broadly applicable strategy to enhance adaptive immunity against cancer and other diseases.

Development of a Cancer Nanovaccine to Induce Antigen-specific Immune Responses Based on Large-Sized Porous Silica Nanoparticles.

Cancer vaccine is one of the immunotherapeutic strategies aiming to effectively deliver cancer antigens to professional antigen-presenting cells such as dendritic cells (DCs), macrophages, and B cells to elicit a cancer-specific immune response. Despite the advantages of the cancer vaccine that can be applied to various cancer types, the clinical approach is limited due to the non-specific or adverse immune responses, stability, and safety issues. In this study, we report an injectable nanovaccine platform based on large-sized (∼350 nm) porous silica nanoparticles (PSNs). We found that large-sized PSNs, called PS3, facilitated the formation of an antigen supply depot at the site of injection so that a single injection of PSN-based nanovaccine elicited sufficient tumor-specific cell-mediated and humoral immune response. As a result, antigen-loaded PS3 induced successful tumor regression in prophylactic and therapeutic vaccination.