Phosphatidylserine-Engineered Lipid Nanoparticles Enable Systemic mRNA Delivery to the Central Nervous System

Abstract Intravenously administered lipid nanoparticles (LNPs) predominantly accumulate in the liver, limiting mRNA delivery to extrahepatic tissues, particularly the central nervous system (CNS). Here, we report a ligand-free strategy for systemic CNS delivery using phosphatidylserine (PS, 1 mol %)-engineered LNPs, in which cholesterol is replaced with protopanaxadiol (PPD) or ginsenoside Rg2. Following intravenous administration of luciferase mRNA, in vivo and ex vivo bioluminescence imaging demonstrated robust protein expression in both the brain and spinal cord with PS-containing LNPs, whereas PS-free formulations showed minimal CNS-associated expression. Increasing PS content from 1 to 4 mol % reduced brain expression while enhancing splenic accumulation, revealing PS-dependent regulation of LNP biodistribution. These findings establish low-level PS incorporation as a tunable strategy for systemic mRNA delivery to the CNS and provide a potential platform for CNS-targeted nucleic acid therapeutics.