Along with the development of controlled delivery systems for targeted therapy, 'single-strategy' therapy often fails to achieve the desired performance in real body internal environments. In such a case, it is necessary to develop synergistic therapy strategies. Herein, for the first time, we designed and synthesized hyaluronic acid (HA) modified Ag@S-nitrosothiol core-shell nanoparticles for synergistic tumor cell targeted therapy based on photothermal therapy (PTT) and nitric oxide (NO) based chemotherapy. Triggered by near-infrared irradiation (NIR), the Ag core nanoparticle would convert the light to cytotoxic heat via a surface plasmon resonance mechanism for cancer cell apoptosis. Meanwhile, responding to NIR as well as the generated heat, the S-nitrosothiol polymeric shells would give off free NO at high concentration, inducing NO based chemotherapy. Tumor cell selective cytotoxicity assay in vitro as well as tumor bearing mouse experiments in vivo demonstrated the effective photothermal and NO based chemical synergistic tumor targeted therapy. This spatiotemporally controllable system could provide a new option and era for tumor targeted therapy in the future.