Spleen-targeted NeoPol-mL242 mRNA vaccine induces robust T-cell responses in a hepatocellular carcinoma model
Yufei Wu, Gongrui Sun, Wendan Ren, Yang Gui, Cong Wang, Xinyi Ye, Yun Chen, Xiufeng Pang, Qi Zhang, Zijun Wang, Yuxuan Wu
Abstract
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. Schematic illustration of L242-20Lipo for in vivo delivery of personalized neoantigen mRNA. The formulation of spleen-targeted L242-20Lipo and the preparation of personalized neoantigen mRNA vaccines, including B16M01-mL242 for murine melanoma and NeoPol-mL242 for hepatocellular carcinoma, enable precise and effective immune activation.