一种STING增强的脂质纳米颗粒mRNA疫苗用于治疗性癌症疫苗接种

Despite the success of immunotherapies and preventative vaccines in virus-associated cancers, the translation of therapeutic vaccination has been limited, often by limited immunogenicity and inability to overcome the immunosuppressive ‘cold' tumor microenvironment. Recent advances in mRNA vectors for viral immunization, and optimized nanoparticle delivery, have renewed promise for cancer vaccination. In this study, we developed an ionizable stable nucleic acid lipid nanoparticle (SNALP) nanovaccine for the delivery of mRNA-encoded model antigen, ovalbumin (OVA). To counter tumor-associated immunosuppression, we harnessed the innate anti-viral stimulator of interferon genes (STING) pathway by co-encapsulating cyclic dinucleotide STING agonist 2'3'-cGAMP. SNALP formulations were optimized for biocompatibility and cell uptake, with small particle size, near-neutral surface charge, and high encapsulation efficiency of both mRNA and 2'3'-cGAMP within a single platform. SNALP-mediated co-delivery achieved effective mRNA transfection and antigen presentation in primary dendritic cells (DCs) in vitro , whilst addition of 2'3'-cGAMP enhanced DC maturation and activation, noted by increased co-stimulatory (CD80, CD86) and MHC-I (H-2Db, H-2Kb) marker expression. Nanovaccine-activated DCs efficiently primed naïve primary CD8 + T cells to elicit effector function and replicate in co-culture. In vivo , immunization with 2'3'-cGAMP-boosted OVA-SNALPs elicited a robust immunological T cell response, evidenced by circulating antigen-specific CD8 + T cell populations with central memory phenotypes, and effector splenic CD8 + T cells capable of TCR-mediated cytokine production upon challenge. Therapeutic relevance of 2'3'-cGAMP-OVA-SNALPs was assessed in murine models of melanoma expressing OVA (B16F10-OVA) under different vaccination protocols. The nanovaccine consistently delayed tumor onset and extended survival, completely preventing tumor formation when given prophylactically, or driving total tumor regression when given therapeutically by local (intra-tumoral) or systemic (intra-muscular) routes, in a subset of animals, which was not found in non-adjuvanted controls. Some tumor control was also noted upon therapeutic administration of SNALPs containing irrelevant mRNA, highlighting potentially beneficial innate adjuvancy of the platform itself. Altogether, this work shows that SNALP-based nanovaccines are a versatile and translatable platform for next-generation cancer immunotherapy. The nanovaccine showed potential as a monotherapy, converting immunologically ‘cold' tumors into responsive microenvironments. This adaptable system enables co-delivery of antigens and immune modulators to target immunosuppressive and induce durable anti-tumor responses. Future studies will explore combining it with additional immunotherapies to improve clinical efficacy.