A naturally derived lipopeptide lipid nanoparticle platform enabling multiple nucleic acids delivery

Lipid nanoparticles (LNPs) have emerged as versatile platforms for nucleic acid-based therapies. Despite advancements, key challenges remain in achieving tissue-specific delivery while maintaining low toxicity and tunable properties essential for therapeutic applications. Here, we report a novel high-performance LNP platform employing arginine-histidine peptide-dioleoylphosphatidylethanolamine (RmHnC-DOPE) lipopeptides as core components. Through systematic optimization of arginine-to-histidine ratios, we engineered three variants, R3H7C-DOPE, R4H6C-DOPE, and R5H5C-DOPE, enabling payload-specific and tissue-selective delivery of siRNA, mRNA, and plasmid DNA. In vitro evaluation demonstrated superior gene silencing efficiency for R4H6C-DOPE (85.1%) and R5H5C-DOPE (89.5%) compared to benchmark SM-102 LNPs (67.4%), while maintaining >99% cell viability. R5H5C-DOPE exhibited exceptional broad-spectrum delivery, achieving 74.8% and 92.1% transfection efficiency for mRNA and pDNA, respectively. Notably, R3H7C-DOPE showed 11-fold enhanced pDNA expression relative to SM-102. In vivo studies revealed R3H7C-DOPE's superior hepatic targeting, achieving >2-fold greater PCSK9 suppression (14.1 ± 7.3% residual expression at day 28) versus SM-102 (53.8 ± 41.2% at day 7). R5H5C-DOPE demonstrated remarkable extrahepatic targeting with >90% pulmonary localization, effectively overcoming the hepatic tropism of conventional LNPs. Comprehensive safety assessments revealed exceptional biocompatibility of RmHnC-DOPE formulations, with 100% survival rates across mouse strains, contrasting sharply with SM-102-induced severe toxicity and mortality. Long-term studies confirmed sustained tolerability with preserved organ function and minimal inflammatory responses. This versatile platform combines superior biocompatibility, precise tissue targeting, and synthetic accessibility, providing a clinically viable solution for diverse gene delivery applications spanning hepatic silencing and extrahepatic therapeutics.