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Developing safe and effective nonviral gene vector ishighly crucialfor successful gene therapy. In the present study, we designed a seriesof biodegradable micelles based on hybrid polypeptide copolymers ofpoly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) for efficientgene delivery. A group of amphiphilic PEG-PLL-PLLeu hybrid polypeptidecopolymers were synthesized by ring-opening polymerization of N-carboxyanhydride, and the chemical structure of each copolymerwas characterized by 1H NMR and FT-IR spectroscopy measurement.The PEG-PLL-PLLeu micelles were positively charged with tunable sizesranging from 40 to 90 nm depending on the length of PLL and PLLeusegment. Compared with PEG-PLL copolymers, PEG-PLL-PLLeu micellesdemonstrated significantly higher transfection efficiency and lesscytotoxicity. Furthermore, the transfection efficiency and biocompatibilityof the micelles can be simultaneously improved by tuning the lengthof PLL and PLLeu segments. The transfection efficiency of PEG-PLL-PLLeumicelles in vivo was two to three times higher than that of PEI25k, which was attributable to their capability of promotingDNA condensation and cell internalization as well as successful lysosomeescape. Hence well-defined PEG-PLL-PLLeu micelles would serve as highlyeffective nonviral vectors for in vivo gene delivery. [ABSTRACT FROM AUTHOR]