Cascade Self-Generation of Carbon Monoxide Triggered by Photoinduced Holes for Efficient Hypoxic Tumors Therapy

It still remains challenging to design multifunctional therapeutic reagents for effective cancer therapy under a unique tumor microenvironment including insufficient endogenous H₂O₂ and O2, low pH, and a high concentration of glutathione (GSH). In this work, a CO-based phototherapeutic system triggered by photogenerated holes, which consisted of ionic liquid (IL), the CO prodrug Mn₂(CO)₁₀, and iridium(III) porphyrin (IrPor) modified carbonized ZIF-8-doped graphitic carbon nitride nanocomposite (IL/ZCN@Ir(CO)), was designed for cascade hypoxic tumors. Upon light irradiation, the photogenerated holes on IL/ZCN@Ir(CO) oxidize water into H₂O₂, which subsequently induces Mn₂(CO)₁₀ to release CO. Meanwhile, IrPor can convert H₂O₂ to hydroxyl radical (•OH) and subsequent singlet oxygen (¹O₂), which further triggers CO release. Moreover, the degraded MnO₂ shows activity for glutathione (GSH) depletion and mimics peroxidase, leading to GSH reduction and •OH production in tumors. Thus, this strategy can in situ release high concentrations of CO and reactive oxygen species (ROS) and deplete GSH to efficiently induce cell apoptosis under hypoxic conditions, which has a high inhibiting effect on the growth of tumors, offering an attractive strategy to amplify CO and ROS generation to meet therapeutic requirements in cancer treatment.