Sun R, et al. ACS Nano 2020.
Hydrogen gas can mitigate oxidative stress in many diseases that is regarded to be safe and free of side effect. Inspired by a metalloenzyme in a variety of microorganisms, here we propose a photo-activated H2 nanogenerator that comprises a fluorinated chitosan (FCS), a chemotherapeutic drug (Gemcitabine, GEM), and a catalyst of H2 production ([FeFe]TPP) that can form self-assembled [FeFe]TPP/GEM/FCS nanoparticles (NPs). The [FeFe]TPP/GEM/FCS NPs exhibit excellent transmucosal and tumor cell
penetration capacities after intravesical instillation into the bladder, and can efficiently produce H2 gas in situ upon a 660 nm laser irradiation, which significantly enhances the efficacy of hydrogen-chemotherapy of cancer in vitro and in vivo. Moreover, we discover that H2 gas in hydrogen-chemotherapy can inhibit mitochondrial function, hinder ATP synthesis, and cause the reduction of P-gp efflux pump function, which finally attenuate P-gp protein drug transport capacity in cancer cells. This photo-activated H2 evolution in situ to improve the therapeutic efficacy of chemotherapy of bladder cancer may present an effective hydrogen-chemotherapy strategy for cancer treatment.