Peptide–Lipid Nanoparticles Enhance Cell Transfection Efficiency

In recent years, lipid nanoparticles (LNPs) based on ionizable lipids have shown great potential as nonviral nucleic acid delivery carriers in clinical applications, but they still face challenges such as insufficient targeting, immunogenicity, and low efficiency in difficult-to-transfect cells. In this study, we designed and optimized a novel peptide-lipid nucleic acid delivery system (LNP-pep). Through combinatorial synthesis of an ionizable lipid library from amine head groups and alkyl acrylates, we identified G12 as a highly efficient ionizable lipid and optimized the formulation with DOPE as the helper lipid to establish a potent LNP platform. A rationally designed amphiphilic peptide, C16-LGKRGD, was synthesized and incorporated into the LNP system via a hydrophobic coassembly strategy. The resulting LNP-pep formulation achieved efficient mRNA transfection in difficult-to-transfect cell lines, including PC-12 and MCF-7, outperforming unmodified LNPs and commercial reagents. Furthermore, LNP-pep exhibited ideal physicochemical properties and enhanced cellular uptake through an integrin-mediated cooperative endocytosis mechanism. This study provides a new strategy for the development of efficient and low-toxicity multifunctional nucleic acid delivery systems, highlighting the importance of both lipid library screening and rational peptide design in achieving synergistic delivery enhancement.