Spleen-targeted NeoPol-mL242 mRNA vaccine induces robust T-cell responses in a hepatocellular carcinoma model.

Personalized neoantigen peptide vaccines have shown remarkable anti-tumor activity across diverse cancer types. With the rapid advancement of messenger RNA (mRNA) delivery technologies during the coronavirus disease of 2019 (COVID-19) pandemic, mRNA-based cancer vaccines have emerged as a promising therapeutic approach because of their scalable production, safety, and capacity to elicit potent immune responses. However, the predominant distribution of mRNA delivery systems in the liver may lead to hepatic damage and restrict therapeutic accessibility. In this study, we designed a novel ionizable lipid library to shift the delivery to the spleen. By incorporating an additional anionic lipid, we identified an optimized vaccine formulation, which exhibited efficient uptake by dendritic cells (DCs). Notably, this formulation achieved spleen-selective delivery without requiring targeting ligand modifications, thereby minimizing cytotoxicity risks. Furthermore, the spleen-targeted L242-20Lipo nanoparticle was employed to facilitate the efficient delivery of personalized neoantigen mRNA vaccines. Evaluation in a hepatocellular carcinoma (HCC) model demonstrated that the NeoPol-mL242 mRNA vaccine elicited potent anti-tumor immunity while maintaining an excellent safety profile. These results highlight NeoPol-mL242 as a promising candidate for application in cancer immunotherapy.