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A comb-like amphiphilic copolymer methoxypolyethylene glycol- graft -poly( l -lysine)- block -poly( l -phenylalanine) (mPEG- g -PLL- b -Phe) was successfully synthesized. To synthesize mPEG- g -PLL- b -Phe, diblock copolymer PLL- b -Phe was first synthesized by successive ring-opening polymerization of α-amino acid N-carboxyanhydrides followed by the removal of benzyloxycarbonyl protecting groups, and then mPEG was grafted onto PLL- b -Phe by reductive amination via Schiff's base formation. The chemical structures of the copolymers were identified by 1 H NMR. mPEG- g -PLL- b -Phe copolymer had a critical micelle concentration of 6.0 mg/L and could self-assemble in an aqueous solution into multicompartment nanomicelles with a mean diameter of approximately 78 nm. The nanomicelles could encapsulate doxorubicin (DOX) through hydrophobic and π–π stacking interactions between DOX molecules and Phe blocks and simultaneously complex P-gp siRNA with cationic PLL blocks via electrostatic interactions. The DOX/P-gp siRNA-loaded nanomicelles showed spherical morphology, possessed narrow particle size distribution and had a mean particle size of 120 nm. The DOX/P-gp siRNA-loaded nanomicelles exhibited pH-responsive release behaviors and displayed accelerated release under acidic conditions. The DOX/P-gp siRNA-loaded nanomicelles were efficiently internalized into MCF-7 cells, and DOX released could successfully reach nuclei. In vitro cytotoxicity assay demonstrated that the DOX/P-gp siRNA-loaded nanomicelles showed a much higher cytotoxicity in MCF-7 cells than DOX-loaded nanomicelles due to their synergistic killing effect and that the blank nanomicelles had good biocompatibility. Thus, the novel comb-like mPEG- g -PLL- b -Phe nanomicelles could be a promising vehicle for co-delivery of chemotherapeutic drug and genetic material. [ABSTRACT FROM AUTHOR]