Science China. Life sciencesOct 13, 2026

Improving fat-based particles to lower liver buildup and boost mRNA delivery at target sites

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 14, 2026

Abstract

The optimized formulation SM102M significantly reduced liver-associated signal compared to the parental formulation SM102.

SM102M preserved or enhanced local expression after local delivery across various administration routes.
Localized gene delivery and editing were supported by SM102M with minimal liver-associated signal.
The altered distribution of SM102M is linked to reduced binding with apolipoprotein E and lower systemic exposure.
Diminished lysosomal escape in liver cells was observed with the SM102M formulation.
SM102M demonstrated favorable tolerability and maintained delivery performance even with repeated use.

Simplified

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.

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A tweaked LNP formula cut liver accumulation while keeping local delivery intact

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Improving fat-based particles to lower liver buildup and boost mRNA delivery at target sites

Abstract

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