Mitochondria-targeted carbon monoxide delivery combined with iron chelation therapy for cancer synergistic treatment.

Carbon monoxide (CO) effectively induces mitochondrial metabolic collapse by disrupting oxidative phosphorylation for cancer therapy, while its clinical translation is hindered by inefficient mitochondrial delivery and redox homeostasis maintained via mitochondrial iron regulation. To overcome these limitations, we engineered a mitochondria-targeted CO delivery strategy synergized with deferasirox (DFX)-mediated iron chelation. A mitochondria-directed CO donor, TPPMnCO, was synthesized by coordinating manganese carbonyl complexes with a triphenylphosphine-derived ligand (TPPPy). Subsequently, TPPMnCO and DFX were covalently attached to nitrogen-doped graphene quantum dots (N-GQDs), yielding a multifunctional nanoplatform DFX@TPPMnCO@N-GQDs. Under 808 nm NIR irradiation, this nanoplatform selectively accumulates in tumor mitochondria, triggering CO release to induce apoptosis while DFX disrupts iron homeostasis, synergistically amplifying mitochondrial metabolic failure. In vitro and in vivo studies confirmed the nanoplatform's biosafety and excellent tumor suppression efficacy, establishing a paradigm-shifting strategy for gas therapy via iron homeostasis modulation.