Harnessing Topology and Stereochemistry of Glycidylamine-Derived Lipid Nanoparticles for in Vivo mRNA Delivery to Immune Cells in Spleen and Their Application for Cancer Vaccination

mRNA lipid nanoparticles (LNPs) have reached an inflection point and are now paving the way for a new wave of precision therapies. The design of nonhepatocyte RNA delivery systems without targeting ligands, however, remains a challenge. It is reported that the development of ligand-free glycidylamine (GA) derivatives containing LNPs (GA-LNPs) that preferentially deliver mRNA to immune cells in the spleen. Notably, it is demonstrated that the stereochemistry of GA-lipids has a significant impact on their self-assembly and in vitro and in vivo RNA delivery efficiency and tropism. This impact is dependent on the monomeric structure of GA and number of stereogenic centers. Furthermore, the nonlinear topology of GA lipid derivatives induced a sevenfold improvement in mRNA delivery efficiency. The top-performing estriol-GA05-30 LNPs elicited strong antitumor activity in a therapeutic and prophylactic cancer model and are well tolerated in mice. These results highlight the significance of the chemistry of ionizable lipids for extrahepatic RNA delivery and indicated a promising direction for the development of next-generation mRNA immunotherapies.