Developing safe, effective drug and nonviral gene vectors are highly crucial for successful chemical drug therapy and gene therapy.Here we designed and synthesized a new type of nanocarriers based on hybrid polypeptide copolymers methoxy poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine) (MPEG-b-PLL-b-PLLeu) as highly effective drug and gene vectors.MPEG-b-PLL(Z) copolymers first were synthesized by ring opening polymerization of LLys(Z)-NCA using MPEG-NH2 as initiator.The MPEG-b-PLL(Z)-b-PLLeu copolymers were fabricated via further ring opening polymerization of LLeu-NCA initiated by MPEG-b-PLL(Z).The MPEG-b-PLL-b-PLLeu copolymers were then obtained by MPEG-b-PLL(Z)-b-PLLeu deprotection.The nanoparticle micelles were prepared via the copolymers dissolved in DMSO and then dialyzed in water.The hydrophobic PLLeu core entrapped with anticancer drugs, while the PLL polypeptide cationic backbone allowed for electrostatic interaction with the negatively charged pDNA.The micelles with hydrodynamic size 61.6 nm and the zeta potential was about +40mV.With the decrease of pH, DOX release rate was accelerated due to amino groups of the lysine residues protonated dramatically.The MPEG-b-PLL-b-PLLeu polymeric micelles bonded pDNA completely at ratio of N/P above 1 and the gene transfection experiments demonstrated that the polymeric micelles with longest PLL segments could be the most effective gene nanocarriers.Hence, cationic micelles based on MPEG-b-PLL-b-PLLeu hybrid polypeptides were excellent carriers for hydrophobic drug and gene delivery.