Multiblock Copolypeptides as Efficient Gene Carriers: Impact of Hydrophobic Fraction and Distribution

Cationic polymers are widely studied as gene delivery carriers due to their low immunogenicity and facile structural modulation. The hydrophobic modification of cationic polymers is an effective strategy to optimize the transfection efficiency. However, the fine-tuning of the hydrophobic–hydrophilic balance to improve the transfection remains largely unexplored. In this article, we reported the enhanced performance of poly(l-lysine) (PLL), one of the first polymeric gene vectors with low potency, through the incorporation and modulation of hydrophobic blocks. Both the fraction and the distribution of hydrophobic blocks were critical, which influenced the condensation of DNA and the internalization of polyplexes. With proper hydrophobicity design, the multiblock copolypeptide exhibited 2–3 orders of magnitude higher transfection efficiency than its PLL analogue, mediating effective intracellular delivery of the p53 gene to inhibit the growth of tumor cells. This study highlights hydrophobic modification to boost the potency of cationic polymers, providing insights into the control over the hydrophobic–hydrophilic balance in the design of polymeric gene vectors.