Multi-functional lipid nanoformulations for enhancing the efficacy of mRNA tumor vaccines by reversing tumor immunosuppressive microenvironment

mRNA tumor vaccines relying solely on the immune killing effect are inadequate for achieving efficient tumor suppression, primarily because tumor immunosuppressive microenvironment (TIME) significantly impedes the function of Cytotoxic T lymphocytes. To enhance the efficacy of mRNA vaccines, we developed a tumor-targeted nanoformulation co-loaded with a CPT-derived SN38 prodrug and siPD-L1 (RSLNP/siPD-L1) for co-administration with mRNA vaccines. Low-dose SN38 not only inhibits the proliferation of tumor cells but also induces immunogenic cell death, which, in combination with siPD-L1-mediated immune checkpoint blockade can jointly reverse TIME. Antitumor studies showed that RSLNP/siPD-L1 increased the tumor inhibition rate of mRNA vaccines by 47.7 % in melanoma-bearing mice and by 26.1 % in breast cancer-bearing mice. Immune analysis indicated that RSLNP/siPD-L1 not only promoted the maturation of local antigen-presenting cells as well as the secretion of immune factors, but also enhanced the infiltration, activation, and killing effects of cytotoxic lymphocytes in the tumor microenvironment, transforming “cold tumors” into “hot tumors”. The developed RSLNP/siPD-L1 significantly enhances the antitumor efficacy of mRNA vaccines and provides a new strategy for clinical cancer treatment.