Impact of Lipid\nTail Length on the Organ Selectivity\nof mRNA-Lipid Nanoparticles

The delivery of mRNA molecules to organs beyond the liver\nis valuable\nfor therapeutic applications. Functionalized lipid nanoparticles (LNPs)\nusing exogenous mechanisms can regulate <i>in vivo</i> mRNA\nexpression profiles from hepatocytes to extrahepatic tissues but lead\nto process complexity and cost escalation. Here, we report that mRNA\nexpression gradually shifts from the liver to the spleen in an ionizable\nlipid tail length-dependent manner. Remarkably, this simple chemical\nstrategy held true even when different ionizable lipid head structures\nwere employed. As a potential mechanism underlying this discovery,\nour data suggest that 1,2-distearoyl-<i>sn</i>-glycero-3-phosphocholine\n(DSPC) is enriched on the surface of mRNA/LNPs with short-tail lipids.\nThis feature limits their interaction with biological components,\navoiding their rapid hepatic clearance. We also show that spleen-targeting\nLNPs loaded with SARS-CoV-2 receptor-binding domain (RBD) mRNA can\nefficiently induce immune responses and neutralize activity following\nintramuscular vaccination priming and boosting.