Optimization of lipid nanoparticles reduces hepatic accumulation and enhances local delivery of mRNA

Lipid nanoparticles (LNPs) have emerged as the most widely used non-viral gene delivery system, particularly for mRNA therapeutics. However, predominant hepatic accumulation and poor local delivery remain major barriers to their broader application. To address this challenge, we employed a design of experiments (DOE) strategy to systematically refine LNP composition and identified an optimized formulation, SM102M. Compared with the parental SM102 formulation, SM102M markedly reduced liver-associated signal after both intramuscular and intravenous administration, while preserving or enhancing local expression after local delivery. Across multiple local administration routes, including intramuscular, intracerebroventricular, and intravitreal injection, SM102M supported localized gene delivery and gene editing with minimal liver-associated signal. Mechanistically, the altered biodistribution of SM102M was associated with reduced apolipoprotein E (ApoE) binding, lower systemic exposure, and diminished lysosomal escape in hepatocytes. SM102M also showed favorable tolerability and maintained local delivery performance under repeated administration. Together, these findings establish DOE as a practical framework for rational LNP engineering and identify a formulation with reduced hepatic reporter expression and improved local delivery performance.