Responsive Multivesicular Polymeric Nanovaccines that Codeliver STING Agonists and Neoantigens for Combination Tumor Immunotherapy

Abstract

Immune checkpoint blockade (ICB) has significantly advanced cancer immunotherapy, yet its patient response rates are generally low. Vaccines, including immunostimulant‐adjuvanted peptide antigens, can improve ICB. The emerging neoantigens generated by cancer somatic mutations elicit cancer‐specific immunity for personalized immunotherapy; the novel cyclic dinucleotide (CDN) adjuvants activate stimulator of interferon genes (STING) for antitumor type I interferon (IFN‐I) responses. However, CDN/neoantigen vaccine development has been limited by the poor antigen/adjuvant codelivery. Here, pH‐responsive CDN/neoantigen codelivering nanovaccines (NVs) for ICB combination tumor immunotherapy are reported. pH‐responsive polymers are synthesized to be self‐assembled into multivesicular nanoparticles (NPs) at physiological pH and disassembled at acidic conditions. NPs with high CDN/antigen coloading are selected as NVs for CDN/antigen codelivery to antigen presenting cells (APCs) in immunomodulatory lymph nodes (LNs). In the acidic endosome of APCs, pH‐responsive NVs facilitate the vaccine release and escape into cytosol, where CDNs activate STING for IFN‐I responses and antigens are presented by major histocompatibility complex (MHC) for T‐cell priming. In mice, NVs elicit potent antigen‐specific CD8 + T‐cell responses with immune memory, and reduce multifaceted tumor immunosuppression. In syngeneic murine tumors, NVs show robust ICB combination therapeutic efficacy. Overall, these CDN/neoantigen‐codelivering NVs hold the potential for ICB combination tumor immunotherapy.

Polymeric nanoparticle-based nanovaccines for cancer immunotherapy

“…Recently, Su et al designed a pH-responsive CDN/neoantigen co-delivering nanovaccine (NV) composed of cationic poly(2-(dimethylamino)ethyl methacrylate) (PDMA), PEG and poly(2-(diisopropylamino)ethyl methacrylate) (PDPA), which was co-loaded with the STING agonist cyclic GMP-GMP (cGAMP) and neoantigen peptides. 104 NVs efficiently delivered cGAMP and neoantigens to primed LNs, and in the acidic endosomes of APCs, the ultrasensitive pHresponsiveness of PDPA chains triggered the breakdown of NVs, facilitating the release and endosomal escape of cGAMP and Another widely adopted strategy to enhance endo/lysosomal escape and antigen cross-presentation is the redox-sensitive delivery system. 105 Compared with the extracellular environment, the concentration of reducing agents (e.g., glutathione (GSH) and cysteine) is higher in the cytoplasm and late endosomes.…”

Molecularly Stimuli-Responsive Self-Assembled Peptide Nanoparticles for Targeted Imaging and Therapy

“…For example, SAPs have been designed to assemble as nanofibers twined around the cells/organelle to prevent tumor metastasis or cause cell death . For tumor-induced immunosuppression, SAPs have also been developed to target tumor cells or antigen-presenting cells (APCs) to activate local or systemic immune responses. , …”

“…to target tumor cells or antigen-presenting cells (APCs) to activate local or systemic immune responses. 112,113 SAPs utilize a bottom-up strategy to create exquisite nanosized delivery systems 114 that enable them to carry cargo with high loading and low leakage. The stimuliresponsive properties of SAPs enable tumor-targeted and programmable cargo release.…”

Rough Nanovaccines Boost Antitumor Immunity Through the Enhancement of Vaccination Cascade and Immunogenic Cell Death Induction

“…For example, adjuvants including cytosine-phosphateguanine (CpG), R837 (imiquimod), R848 (resiquimod), and cyclic Dinucleotide are codelivered with antigens to induce DC maturation. [9][10][11][12][13][14][15] It is to be noted that the intrinsic properties of nanoparticles have been exploited to promote the efficiency of the vaccination cascade. Nanoparticles with an appropriate size of 20 to 200 nm are supposed to preferably drain and accumulate to lymph nodes, [16][17][18] while asymmetrical morphology, positive surface, elasticity, and deformability facilitate the cellular uptake of nanovaccines.…”