mRNA therapy offers a promising platform for developing highly effective and personalized treatments for diverse diseases. This study employed two strategies—chemical lipidation and physical lipid doping—to introduce lipid components into modular lysine-histidine-based peptide systems, for developing economical, safe, efficient, and targeted mRNA carriers and systematically investigating the effects of peptide and lipid modules on mRNA delivery efficiency both 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 corresponding pure peptide system. Utilizing a physical strategy, the top-performing formulation demonstrated a transfection efficiency superior to that of the pure lipid and 43.9 times greater than its pure peptide counterpart. It also outperformed commercial reagents in mRNA expression intensity. In vivo, the optimal physical composite system, with simplicity, cost-effectiveness and safety, enabled efficient lung-targeted mRNA delivery, showing great potential for advancing mRNA therapy of lung-related diseases. This study provides a broader perspective on the design of functional peptide-based gene delivery systems.
