Along with development of the controlled delivery systems for target therapy, ‘single-strategy’ therapy often fails to achieve the desired performance in real body internal environment. In such case, it is necessary to develop synergistic therapy strategies. Herein, for the first time, we designed and synthesized hyaluronic acid (HA) modified Ag@S-nitrosothiols core-shell nanoparticles for synergistic tumor cells target 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 in a surface plasmon resonance mechanism for cancer cells apoptosis. Meanwhile, responsive to NIR as well as the generated heat, the S-nitrosothiols polymeric shells would give off free NO in high concentration, inducing NO based chemotherapy. Tumor cells selective cytotoxicity assay in vitro as well as the tumor bearing mice experiments in vivo demonstrated the effective photothermal and NO based chemical synergistic tumor targeting therapy. This spatiotemporally controllable system would provide a new option and era for tumor target therapy in future.