Self-Assembly of Virus-like Nanoparticles for Nucleic Acid Delivery Based on De Novo Designed α-Helix Peptides

Efficient and safe delivery of nucleic acids remains a major challenge for clinical translation of gene therapies. Here, we report de novo-designed α-helical peptides that coassemble with lipids and nucleic acids to form core-shell, virus-like nanoparticles (VLNs). The peptides combine a cationic N-terminus for nucleic acid binding, an anionic C-terminus for lipid coordination, and pH-responsive residues that promote endolysosomal escape. The resulting VLNs achieved up to 91.2% mRNA transfection and 93.1% siRNA-mediated gene knockdown in vitro, outperforming Lipofectamine 2000. This work demonstrates a programmable, rational design strategy to produce virus-mimetic nanocarriers that address key extracellular and intracellular barriers in nucleic acid therapeutics.