Microbiome Metabolite-Incorporated Lipid Nanoparticles Augment CD8+ T Cell Memory Potential and Immunity for mRNA Cancer Vaccines

Recently, mRNA/lipid nanoparticle (LNP)-based vaccines have been successfully applied to prevent infectious diseases, and several types of neoantigen-encoding mRNA Cancer vaccines are currently under clinical trials. While mRNA vaccines effectively induce adaptive immune responses to antigens, mRNA vaccine-induced immunity is shortly maintained, and the longevity of the immune memory, especially improving the CD8⁺ T cell memory potential, could be even more important. Previously, microbiome metabolites have shown T cell memory potential-augmenting effects via regulating the immunometabolism. Herein, we develop microbiome metabolite-incorporated LNPs (mmi-LNPs) and evaluate their potential to enhance T cell memory responses following mRNA vaccination. In various ionizable LNP formulations, mmi-LNPs elicited more stem cell-like memory T cells (T-SCMs) and augmented central and effector memory T cell responses, which indicates the general applicability of mmi-LNPs. Notably, butyrate-incorporated mmi-LNP exhibited the strongest effects. In conclusion, we suggest microbiome metabolite-incorporated LNP as a next-generation delivery vehicle for mRNA vaccines.