Specific Generation of Singlet Oxygen through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu‐TCPP Nanosheets for Cancer Therapy

Abstract The generation of singlet oxygen ( 1 O 2 ) during photodynamic therapy is limited by the precise cooperation of light, photosensitizer, and oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells. Herein, we report that an ultrathin two‐dimensional metal–organic framework of Cu‐TCPP nanosheets (TCPP=tetrakis(4‐carboxyphenyl)porphyrin) can selectively generate 1 O 2 in a tumor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H 2 O 2 followed by reduction to peroxyl radicals under the action of the peroxidase‐like nanosheets and Cu 2+ , and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently, the Cu‐TCPP nanosheets can selectively destroy tumor cells with high efficiency, constituting an attractive way to overcome current limitations of photodynamic therapy.