Red-Light-Triggered Microenvironment-Responsive Sustained Carbon Monoxide Release for Enhanced Tumor Therapy

Abstract

Carbon monoxide (CO), a gasotransmitter, has gained attention as a potential therapeutic agent in cancer treatment. The precise and sustained release of CO is crucial for minimizing its toxicity and enhancing its therapeutic efficacy. We have developed a light-gated, microenvironment-responsive CO release platform for precise and sustained CO delivery. FeCO was used as the CO donor and integrated into the micelle core containing tertiary amine (TA) residues and a Pd-based photosensitizer (PdTPTBP). In the first stage, the H₂O₂ generated during light irradiation, in combination with GSH, triggers the release of CO and Fe²⁺ from FeCO. Subsequently, Fe²⁺ reacts with H₂O₂ via a Fenton reaction, further promoting sustained CO release under dark conditions in the second stage. Light irradiation acts as a gating mechanism to achieve precise and sustained CO release. This CO delivery platform can be efficiently internalized by 4T1 tumor cells and, upon 630 nm light irradiation, releases CO intracellularly to induce ferroptosis. By synergistically disrupting mitochondrial function, it exhibits effective antitumor activity in 4T1 tumor-bearing mice.