4.7 Article

Synthetic Helical Polypeptide as a Gene Transfection Enhancer

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BIOMACROMOLECULES
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AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.2c00331

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  1. National Key R&D Program of China [2021YFB3800900]
  2. National Natural Science Foundation of China [51925305, 51873208, 51833010, 51803210]

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This study developed a facile and effective strategy to construct polymeric gene delivery systems with high transfection efficiency. It was found that a cationic polypeptide with a stable alpha-helical conformation significantly improved the cellular uptake and endosomal escape of polymeric gene delivery systems, thereby enhancing transfection efficiency.
The relatively low transfection efficiency limits further application of polymeric gene carriers. It is imperative to exploit a universal and simple strategy to enhance the gene transfection efficiency of polymeric gene carriers. Herein, we prepared a cationic polypeptide poly(gamma-aminoethylthiopropyl-L-glutamate) (PALG-MEA, termed PM) with a stable alpha-helical conformation, which can significantly improve the gene transfection efficiency of cationic polymers. PM can be integrated into polymeric gene delivery systems noncovalently through electrostatic interactions. With the assistance of PM, polymeric gene delivery systems exhibited excellent cellular uptake and endosomal escape, thereby enhancing transfection efficiency. The transfection enhancement effect of PM was applicable to a variety of cationic polymers such as polyethylenimine (PEI), poly-L-lysine (PLL), and polyamidoamine (PAMAM). The ternary gene delivery system PM/pshVEGF/PEI exhibited an excellent antitumor effect against the B16F10 tumor model. Moreover, we demonstrated that PM could also enhance the delivery of gene editing systems (sgRNA-Cas9 plasmids). This work provides a facile and effective strategy for constructing polymeric gene delivery systems with a high transfection efficiency.

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