Cancer resistance has been the huge challenge to clinical treatment. A photothermal therapy of second near-infrared (NIR-II) organic dye small molecule has been used to conquer the cancer resistance. However, the available NIR-II dye lacks selectivity and spreads throughout the body. It has toxicity and indiscriminate burn injuries normal cells and tissues during therapy. Hence, to improve the therapeutic outcomes, herein, for the first time, we report the mannose-modified zwitterionic nanoparticles loading IR1048 dye, aiming to overcome cancer cellular resistance. The targeting molecule mannose has been applied to modify zwitterionic polyester, and the obtained polyester is employed to load IR1048 to prolong the circulation time in the blood and improve the stability of loaded dye, due to the good cytocompatibility of polyester and the antifouling properties of zwitterions. In vitro experimental results show that the pH-responsive targeted nanoparticles display satisfactory photophysical properties, prominent photothermal conversion efficiency (44.07%), excellent photothermal stability, negligible cytotoxicity for normal cells and strong photothermal toxicity to drug-resistant cancer cells. Moreover, due to the mannose targeting effect, cancer cells can endocytose the nanoparticles effectively. All these results demonstrate potential application of this alternative hyperthermal delivery system with remote-controllable photothermal therapy of tumor for accurate diagnosis by NIR-II fluorescence imaging.