Developing gene vectors with high transfection efficiency and low cytotoxicity to humans is crucial to improve gene therapy outcomes. This study set out to investigate the use of cationic polypeptide bilayer assemblies formed by coil-sheet poly(l-lysine)-block-poly(l-benzyl-cysteine) (PLL-b-PBLC) as gene vectors that present improved transfection efficiency, endosomal escape, and biocompatibility compared to PLL. The formation of the polyplexes was triggered by hydrogen bonding, hydrophobic interactions, and electrostatic association between the cationic PLL segments and the negatively charged plasmid encoding p53, resulting in self-assembled polypeptide chains. Transfection efficiency of these polyplexes increased with increments of PLL-to-PBLC block ratios, with PLL15-b-PBLC5 bilayers exhibiting the best in vitro transfection efficiency among all, suggesting that PLL-b-PBLC bilayer assemblies are efficient in the protection and stabilization of genes. The polypeptide bilayer gene vector reversed the cisplatin sensitivity of p53-null cancer cells by increasing apoptotic signaling. Consistent with in vitro results, mouse xenograft studies revealed that PLL15-b-PBLC5/plasmid encoding p53 therapy significantly suppressed tumor growth and enhanced low-dose cisplatin treatment, while extending survival of tumor-bearing mice and avoiding significant body weight loss. This study presents a feasible gene therapy that, combined with low-dose chemotherapeutic drugs, may treat genetically resistant cancers while reducing side effects in clinical patients.
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