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.

Among the strategies for the treatment of bacterial infections, antibiotics are one of the preferred options. With prolonged use, however, antibiotic resistance has become a growing problem, especially the significant antibacterial activity loss against acidity associated bacterial infections. Herein, surface charge switchable nitric oxide (NO)-releasing nanoparticles (PNBNPs) were designed and synthesized. With the protection of the surface charge switchable shell, the PNBNPs maintain weak negative surface charge and “silent” status during transmission under normal physiological pH conditions. In an acidic environment, the surface polymeric shell is protonated, giving it a positively charged surface, and this benefits the binding of the PNBNPs with the negatively charged bacterial surface. In contrast to the significant antibacterial activity loss of antibiotics in acidic environments, the PNBNPs trigger faster NO release to form highly reactive oxynitride species (such as N₂O₃, NO₂ ⁻, OONO⁻, etc.), causing strong membrane disruption and cell apoptosis, leading to intensive antibacterial activity. The PNBNPs demonstrated excellent biocompatibility and acidity-associated bacterial infection targeted treatment, according to the bacteria binding, the antibacterial activity, and normal cell cytotoxicity assays in vitro, as well as investigations into the therapeutic effects in different pH environments in vivo. These responsive NO-releasing nanoparticles will provide a new option for overcoming acidity-associated bacterial infections and antibiotic resistance problems in the future.