Enhanced mRNA vaccine combined with immune checkpoint blockade efficiently suppresses tumor growth and metastasis.

Recently, mRNA vaccines have successfully prevented infectious diseases but remain only adjuvant therapies for cancer due to limited immune killing efficacy. The efficacy of tumor vaccines depends on both the immunogenicity of associated antigens and the delivery efficacy of lipid nanoparticles (LNPs). While next-generation sequencing has optimized neoantigen identification pipelines, most delivery systems still employ LNP formulations originally developed for infectious disease vaccines. Critically, most infectious disease vaccines primarily rely on humoral immunity for prophylaxis, whereas therapeutic tumor vaccines predominantly depend on cellular immunity for tumor eradication. Due to these mechanistic differences, developing delivery systems specifically designed for mRNA tumor vaccines is crucial. Herein, we constructed a mannose-functionalized LNP (MRLNP) that co-delivers tumor antigen-encoding mRNA and the TLR7/8 agonist resiquimod (R848). Mannose modification promotes lymph node drainage and dendritic cell (DC)-targeted uptake. R848 boosts antigen immunogenicity, driving DC maturation and antigen presentation to robustly activate cellular immunity. In the B16F10-OVA subcutaneous tumor model, MRLNP/mOVA vaccine combined with the anti-PD-1 antibody achieved a 93.5% tumor suppression rate. Furthermore, long-term immune memory generated by combination therapy effectively prevented lung metastasis formation in tumor rechallenge experiments. Collectively, this work establishes that MRLNP, as a novel enhanced delivery system, holds great potential for the development of highly effective mRNA tumor vaccines and combination therapies.