Control theGene Delivery and Anticancer Efficacyof Peptides through Chiral Modulation

Incorporating d-amino acids into peptides can influence the intermolecular interactions of peptides, thus determining the morphology and functionality of self-assembled supramolecular structures. Based on this, we propose a modular chirality regulation strategy and designed four chiral peptides by adjusting the chirality of different functional modules. The chirality can control the coassembly of peptides and nucleic acids into virus-like vesicles with controlled diameters and enzyme-responsiveness. Compared with homochiral peptides, the heterochiral peptides with chirality inversion in their hydrophobic domain transformed into more hydrophobic assemblies in response to the highly expressed enzyme matrix metalloproteinase 7 (MMP-7) in cancer cells and showed higher endosomal membrane disruption activity. Moreover, the heterochiral peptides exhibit high efficiency and selectivity in delivering siRNA gene drugs and inhibiting cancer cell growth, achieving a mortality rate of 95% in cancer cells. These results provide a promising strategy for designing peptide-based nucleic acid delivery systems through chiral modulation.