Bioorthogonal Regulated\nMetabolic Balance for Promotion\nof Ferroptosis and Mild Photothermal Therapy

The nanozyme with NADPH oxidase (NOX)-like activity can\npromote\nthe consumption of NADPH and the generation of free radicals. In consideration\nof that the upregulation of glucose-6-phosphate dehydrogenase (G6PD)\nwould accelerate the compensation production of NADPH, for inhibition\nof G6PD activity, our designed bioorthogonal nanozyme can in situ\ncatalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone\n(DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined\nplatform can disrupt NADPH homeostasis, leading to the collapse of\nthe antioxidant defense system in the tumor cells. The enzyme-like\nactivity of PdCuFe is further enhanced when irradiated by NIR-II light.\nThe destruction of NADPH homeostasis can promote ferroptosis and,\nin turn, facilitate mild photothermal therapy. Our design can realize\nNADPH depletion and greatly improve the therapeutic effect through\nmetabolic regulation, which may provide inspiration for the design\nof bioorthogonal catalysis