Light-Activated Polypeptide Carbon Monoxide-Releasing Nanoparticles for Synergistic Manganese-Mediated Fenton-like Reactions in Cancer Therapy

Carbon monoxide, an endogenous gaseous signaling molecule, has attracted increasing attention because of its therapeutic potential for cancer treatment. Herein, we report a photoresponsive nanoparticle constructed from a metal–carbonyl-conjugated polypeptide for synergistic cancer therapy. Upon 650 nm irradiation, the nanoparticle simultaneously releases carbon monoxide and generates catalytically active manganese species. Mechanistically, carbon monoxide impairs mitochondrial function and disturbs cellular bioenergetics, whereas manganese species deplete intracellular glutathione and induce oxidative damage through Fenton-like hydroxyl-radical generation. This dual-action process integrates gas therapy with catalytic therapy, resulting in amplified oxidative stress and efficient tumor cell eradication. Importantly, both in vitro and in vivo experiments demonstrated potent antitumor efficacy and favorable biosafety under red light activation. Collectively, this work provides a promising strategy for the development of photoresponsive nanoplatforms for synergistic cancer therapies.