An mRNA Tumor Nanovaccine Expressing Tumor Antigen Fused With Angiotensin II Facilitates Type 1 Conventional Dendritic Cell-Mediated Anti-Tumor Immunity.

mRNA-based tumor vaccines have shown great potential as a promising immunotherapeutic approach with encouraging preclinical and clinical results. However, how to enhance the antigen presentation efficiency of mRNA-encoded tumor antigens and the intensity of vaccine-induced CD8+ T cell response remains a great challenge. In this study, an antigen-angiotensin II (ANG II) fusion mRNA nanovaccine that can enhance the immunogenicity of tumor antigens to promote CD8+ T cell immunity for effective tumor inhibition is developed. Furthermore, this mRNA nanovaccine is delivered by lipid nanoparticles (LNPs) composed of cationic lipid-like material C1 and L-phenylalanine-based poly (ester amide) 8p4, which promotes the maturation of dendritic cells (DCs) and increases the type 1 conventional DC (cDC1) subpopulation, together enhancing the antigen presentation function of DCs for eliciting potent antigen-specific CD8+ T cell response. Vaccination with the antigen-ANG II mRNA nanovaccine expressing different tumor antigens effectively inhibited tumor growth on multiple mouse tumor models, which was greatly compromised in the cDC1-deficient Batf3-/- mice. Overall, this work provides an antigen-ANG II fusion mRNA tumor nanovaccine platform with remarkable antitumor efficacy via triggering cDC1-mediated CD8+ T cell response.