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N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymer has been extensively studied as drug carrier for tumor therapy. Due to the Enhanced Permeability and Retention (EPR) effect, HPMA copolymer drug conjugates are able to be passively accumulated in the tumor site. Currently, efficient uptake of this polymeric system by the cancer cells remains a big challenge, as HPMA polymer is highly hydrophilic, neutrally charged, and has low affinity towards cell membrane. In this study, selective and enhanced intracellular internalization of the copolymer-drug conjugates was achieved by utilizing a hybrid strategy including ligand modification and stimuli response. This hybrid approach was rationally designed to comprise cationic HPMA copolymer backbone as drug carrier, doxorubicin (Dox) as model drug, hydrazone bond as drug spacer, FQSIYPpIK (FQS) peptide as αvβ3 targeting ligand and 2, 3-Dimethylmaleic Anhydride (DMA) as a shielded/deshielded cationic group. We demonstrated our system exhibited the “seek-and-destroy” tumor tropic behavior by sequentially undergoing the following steps: (i) tumor passive targeting mediated by EPR effect; (ii) charge reversal at tumor extracellular pH of 6.5; (iii) synergistically enhanced cell uptake via electrostatic interaction with cell membrane and FQS ligand-mediated bio-recognition; (iv) drug released in the lysosome; and v) anticancer effect exerted by the targeted delivery of the Dox.