Photoactivated H₂ Nanogenerator for Enhanced Chemotherapy of Bladder Cancer

Hydrogen gas can mitigate oxidative stress in many diseases and is regarded to be safe and free of side effects. Inspired by a metalloenzyme in a variety of microorganisms, here, we propose a photoactivated 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 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 a reduction of the P-gp efflux pump function, which finally attenuates P-gp protein drug transport capacity in cancer cells. This photoactivated H₂ evolution in situ to improve the therapeutic efficacy of chemotherapy of bladder cancer may present an effective hydrogen chemotherapy strategy for cancer treatment.