The development of stimuli-responsive polymeric nanocarriers could significantly enhance drug bioavailability due to improved pharmacokinetics and biodistribution. However, in the drug delivery process, the poor cell uptake of drug-loaded carriers has greatly limited the therapeutic efficiency for anti-cancer applications. Herein, 2,3-dimethylmaleic anhydride (DMMA) is engineered into the well-defined biodegradable amphiphilic block copolymer poly(D,L-lactide)-block-poly(2-aminoethyl methacrylate) (PLA-b-PAEMA) to construct a tumor-acidity activated nanocarrier (PLA-b-PAEMA/DMMA) for potential tumor therapy. After the loading of positively charged DOX center dot HCl into the negatively charged corona structure through electrostatic attraction, this carrier is expected to prolong the blood circulation time and smartly convert surface charge from negative to positive for enhanced tumor cell uptake and targeted drug release. Furthermore, this carrier exhibits additional cytotoxicity for tumor cells after the tumor-acidity activated surface charge-conversion from negative to positive. Thus, this smart carrier is a feasible candidate for potential cancer therapy.