Endogenous-metabolite-inspired polyamine-oleic acid lipids for safe mRNA delivery and PCSK9 gene editing

Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but often rely on synthetic ionizable cationic lipids that pose concerns regarding immunogenicity, metabolic compatibility, and tolerability. Here, we report an endogenous-metabolite-inspired lipid design strategy in which biogenic polyamines, including agmatine, putrescine, cadaverine, spermidine and spermine, were conjugated with oleic acid to generate polyamine-oleic acid lipids for mRNA delivery. Among these candidates, agmatine-oleic acid (Agm-oa) showed the best overall performance, forming LNPs with high mRNA encapsulation efficiency, uniform particle size distribution and robust in vitro transfection activity. Agm-oa displayed behavior distinct from that of classical ionizable lipids, with strong mRNA association likely mediated by its guanidinium-containing headgroup through electrostatic interactions and hydrogen bonding. Beyond its delivery function, Agm-oa retained bioactivity associated with its agmatine-derived headgroup. Notably, agmatine and other bioactive metabolites released during Agm-oa degradation may suppress nitric oxide (NO) generation in macrophages while enhancing NO production in endothelial cells, suggesting that Agm-oa LNPs may confer anti-inflammatory and vascular protective effects following LNP decomposition. Moreover, Agm-oa LNPs-mediated adenine base editor delivery achieved efficient on-target editing at the PCSK9 locus. In hypercholesterolemic mice, Agm-oa LNPs enabled effective in vivo mRNA delivery and significant reduction of circulating LDL-C. Importantly, Agm-oa LNPs demonstrated a highly favorable safety profile compared to the benchmark formulations, with significantly lower serum LDH and IL-6 levels and minimal immunogenicity, alongside no detectable hepatotoxicity after repeated administration. Therefore, Agm-oa LNPs represent a safe, well-tolerated platform for nucleic acid delivery, with intrinsic bioactivity that may synergistically enhance therapeutic performance.