Chemically or physically introducing lipids into lysine-histidine-based peptide systems for safe, efficient and...

mRNA therapy offers a promising platform for developing highly effective and personalized treatments for diverse diseases. In this study, we integrate structurally simple yet functionally complementary peptide and lipid components to enable the construction of a highly efficient mRNA delivery vector with minimal formulation complexity, making it cost-effective. Using both chemical lipidation (i.e., lipopeptide) and physical lipid incorporation to introduce lipid components with complementary functions into simple lysine-histidine modular peptides, we established a versatile library to develop economical, safe, efficient, and targeted mRNA carriers and systematically investigated how peptide and lipid modules jointly affect mRNA delivery in vitro and in vivo. In vitro results demonstrated that lipid components significantly improved the mRNA encapsulation and transfection efficiency of peptides while maintaining good biocompatibility. The chemical optimization strategy yielded a remarkable 5.3-fold enhancement in transfection efficiency over the pure peptide system. Utilizing the physical strategy, the top-performing formulation exhibited higher transfection efficiency than the pure lipid and 43.9-fold greater efficiency than its pure peptide counterpart, further surpassing commercial reagents in mRNA expression intensity. In vivo, the optimal physical composite system achieved improved efficiency and lung selectivity in mRNA delivery compared to the pure lipid system, demonstrating strong potential for advancing mRNA therapy for lung-related diseases. These findings validate the effectiveness of our complementary design strategy and indicate that this approach can be broadly applied to develop additional simple yet highly functional gene-delivery vectors.