Immune Checkpoint Inhibitor as a Fifth Component of Lipid Nanoparticles Enables Lymph Node‐Targeting and Augments mRNA Vaccine Efficacy

mRNA-encapsulated lipid nanoparticles (LNPs) have been used to develop vaccines and therapeutics since the COVID-19 pandemic, and clinical studies have demonstrated therapeutic benefits of mRNA vaccines for various cancers. However, current LNP formulations still require functional modifications to tailor them for therapeutic and vaccine applications. Recently, fifth component-incorporated LNPs were developed to finely tune their functionality, including immunogenicity and organ-targeting ability. Here, biphenyl-structured amphiphilic PDL1 inhibitors are employed as a fifth component to modify LNPs. Amphiphilic PDL1 inhibitor-incorporated, ALC0315-based LNPs show higher lymph node targeting, with a 6.94-fold increase in mRNA expression in the inguinal lymph node, thereby improving lymph node expansion and immune cell infiltration and, consequently, inducing greater mRNA vaccine efficacy. Furthermore, a consistent lymph node-targeting effect of the fifth component-containing LNP was observed across studies using the SM102-based LNP formulation, suggesting its universality. In conclusion, this study demonstrates that PDL1 inhibitor-incorporated fifth-component LNP serves as a next-generation platform for mRNA vaccines.