A novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was demonstrated for intracellular drug delivery. These micelles are composed of an mPEG shell and polypeptide core, characterized by FT-IR, (1)H NMR, fluorescence techniques. TEM. and DLS. Interestingly, they would undergo a fast sheddable process when encounter the reduction sensitive condition, indicated by the aggregation phenomena in the presence of DTT, a reduction agent, which could cleave the disulfide bond between the micellar core and shell and consequently leading to the aggregation of hydrophobic core. Cytotoxicity study revealed that copolymers in this system have good biocompatibility and their self-assembled micelles showed a high drug loading efficiency for DOX, a hydrophobic drug model, and released DOX quantitatively in response to the intracellular level of reducing potential. Cellular uptake experiments demonstrated that the fluorescently labeled micelles could be successfully internalized into human liver carcinoma HepG2 cells, evidenced by confocal laser scanning microscopy. Above results indicate that the copolymers may have great potential in drug delivery to achieve improved cancer therapy. (C) 2011 Elsevier Ltd. All rights reserved.