Tailoring lipid nanoparticles for application-specific mRNA delivery.

Abstract

Expanding the therapeutic landscape of mRNA medicines to diverse applications necessitates delivery systems tailored to distinct biological requirements. However, beyond vaccine applications, current FDA-approved lipid nanoparticles (LNPs) are often directly used as their original vaccine formulations, substantially limiting their therapeutic potential. Rather than pursuing new ionizable lipids with uncertain safety profiles, we propose an application-oriented re-engineering strategy that leverages the clinically validated SM-102 platform, enabling rational LNP optimization for diverse mRNA delivery and therapeutic scenarios. Through systematic modulation of phospholipid component (e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)) and lipid molar ratios, we tailor LNPs for transfection across representative cell types in vitro, systemic administration in vivo, and intramuscular delivery in vivo. Consequently, SM-102/DSPC and SM-102/DOPE LNPs emerge as preferred formulations for RAW 264.7 macrophages and IGROV1 ovarian cancer cells, respectively, achieving up to a 25.6-fold enhanced mRNA delivery over original SM-102 LNPs in vitro. For intravenous administration, optimal SM-102/DSPC LNPs enable 2.3-fold enhanced hepatic mRNA delivery compared to original SM-102 LNPs. In contrast, intramuscular injection preferentially benefits from SM-102/DOPE LNPs, achieving 17.7-fold higher muscular expression and 22.0-fold enhanced lymph node delivery than SM-102 LNPs. All optimized formulations show comparable tolerability to the clinically validated SM-102 LNPs. This study supports an application-specific tailoring platform that enables the rational selection of appropriate mRNA delivery systems for diverse therapeutic scenarios.