Boosting Cancer Cell Ferroptosis with Carbon Monoxide Poisoned Hemoglobin

The peroxidase (POD)-like nanozymes, particularly those with atomic Fe-N_<i>x</i> sites, have demonstrated exceptional catalytic potential in cancer cell ferroptosis. The biodegradable hemoglobin (Hb) is recognized as an Fe-N₅ POD-like nanozyme expected to replace the carbon-based ones, while its uncontrollable catalytic reaction remains a safety concern. Here, inspired by the carbon monoxide (CO) poisoned Hb, we develop a controllable and biodegradable catalytic nanoplatform DPHCO which integrates carboxyhemoglobin (HbCO) and platinum(IV) prodrug into -CH₂SSCH₂- bridged dendritic mesoporous organosilica nanoparticles (DMON). The Fe-N₅ site of HbCO could be temporarily deactivated during the blood circulation. In tumor tissue, the poisoned site will be in situ reactivated by the H₂O₂-driven valence modulation of heme iron, along with CO desorption. The reactivated Hb performs POD-like activity during the ferric-ferryl redox cycle, adhering to Michaelis-Menten kinetics and density function theory (DFT) calculation results. Both in vitro and in vivo data suggest that the reactivated Hb and released CO could induce lipid peroxidation and cancer cell ferroptosis, which is further boosted by cisplatin synergy. This gas modification and iron valence-driven modulation provide a feasible approach for toggling the "OFF/ON" activity of the catalytic site, which would inspire the development of nanozymes for precision oncotherapy.