Vitamin A-spermine conjugated lipid nanoparticles for efficient nucleic acid delivery in ocular and hepatocellular cells.

Lipid nanoparticles (LNPs) currently represent the predominant delivery strategy for clinically approved nucleic acid drugs. However, the inherent limitations in targeting, low lysosomal escape efficiency, and potential immunogenic risks pose significant challenges to the broader applications of LNP technology. Vitamin A and spermine are endogenous small molecules that all have shown potentials for low toxicity and efficient drug delivery. In this study, we constructed a series of novel VA-linker-Sper lipids through the conjugation of vitamin A and spermine. With the helper lipid dioleoylphosphatidyl ethanolamine (DOPE), we successfully developed a nucleic acid delivery reagent, VA-6C-Sper/DOPE. Mediated by the vitamin A receptor, this reagent achieved highly efficient delivery of both siRNA and plasmids in hepatocellular carcinoma cells (HepG2) and retinal pigment epithelial cells (ARPE19). The cellular uptake and gene regulation effects with VA-6C-Sper were far superior exceeded those of the commercial transfection reagent Lipofectamine. This work provides a foundation for the nucleic acid drug treatment of ocular diseases that are dependent on vitamin A metabolism.