The efficient delivery of chemotherapeutic drugs to the tumor tissues unavoidably encounters numerous obstacles, such as poor tumor targeting capability, slow intracellular drug release and massive accumulation in the liver. In this study, by self-assembling methoxy poly (ethylene glycol)-poly (lactide) block copolymer (mPEG-PLA) and hyaluronic acid-paclitaxel conjugate (HA-PTX), the composite nanoparticles (mPPHP NPs) were fabricated for efficient therapy of cancer. mPPHP NPs formed self-assembled nanoparticles (116 nm in diameter) with a narrow size distribution; and showed a rapid release of PTX in the presence of hyaluronidase and esterase. mPPHP NPs exhibited enhanced internalization by cells via CD44 receptors and selected cytotoxicity against A549 cells in vitro. More importantly, compared with other PTX formulations, mPPHP NPs were demonstrated to present the reduced liver accumulation, excellent tumor-targeting ability and superior antitumor efficacy in vivo, with a TIR of 75.9%. The multifunctional composite nanoparticles could be developed as a promising nano-carrier for improved therapeutic efficacy.