Carbon monoxide (CO)-Strengthened cooperative bioreductive anti-tumor therapy via mitochondrial exhaustion and hypoxia induction.

Bioreductive chemodrugs require hypoxic conditions to activate their anti-cancer efficacy. The insufficient and heterogeneous hypoxic condition in tumor tissues hurdles the therapeutic potency of bioreductive chemodrugs. We herein report a NIR light-triggered CO release system based on mesoporous Prussian blue nanoparticles (PB NPs) to enable cancer-selective hypoxia aggravation and hypoxia-responsive activation of bioreductive anti-cancer drug, tirapazamine (TPZ). Pentacarbonyl iron (Fe(CO)5) was coupled to PB NPs via coordination interaction, and TPZ was encapsulated into the pores of PB NPs. To prolong blood circulation and improve tumor accumulation, the PB-CO-TPZ NPs were surface-decorated with PEG-NH2. Upon tumor site-specific light irradiation, the non-lethal photothermal effect of PB NPs released CO, which accelerated mitochondrial oxygen consumption and generated hypoxia to activate TPZ. The CO-induced mitochondrial exhaustion simultaneously led to cancer cell apoptosis, thus realizing synergistic anti-cancer effect with TPZ-mediated bioreductive chemotherapy. To the best of our knowledge, it is the first time to activate bioreductive chemotherapy using CO. This study thus provides a promising paradigm to realize effective and safe cancer treatment via precise manipulation of drug activities, and may open new insights in the use of CO for biomedical treatment.