Alkylated RALA-Derived\nPeptides for Efficient Gene\nDelivery

RALA\nis an amphipathic cationic peptide demonstrated to be a low-toxicity\nand high-efficiency delivery platform for the systemic delivery of\nnucleic acid therapeutics. This work reports three RALA-derived peptides\nmodified with N-terminal palmitic acid, engineered through amino acid\nsubstitutions and truncated sequences. All three peptides have good\nnucleic acid encapsulation, release and uptake, biocompatibility,\nand endolysosome escape. The siRNA transfection efficiency is about\n90%, and the silencing rate of GA (C16-GLFWHHHARLARALARHLARALRA) exceeds\nthat of lipofectamine 2000 (siRNA concentration = 50 nM). Truncating\nthe peptide chain while retaining a certain amount of arginine ensures\nan effective particle size. Replacing glutamic acid with three histidines\nensures an effective zeta potential and accelerates the endosome escape\nprocess through the proton sponge phenomenon. Introducing phenylalanine\nenhances the carrier–cell interaction. We believe that they\nare powerful carriers of siRNA therapy and may have good application\nprospects in treating various diseases.