Blocking glutathione regeneration: Inorganic NADPH oxidase nanozyme catalyst potentiates tumoral ferroptosis

Emerging cancer cell ferroptosis features the direct depletion of glutathione (GSH) and resultant chemical inhibition on glutathione peroxidase 4 (GPX4) bioactivity, which, unfortunately, is counteracted considerably by nicotinamide adenine dinucleotide phosphate (NADPH)-enabled regeneration of antioxidant GSH. Herein, a Pt-MIL-101 (Fe)-based nanocatalytic medicine (NCM) is proposed to catalyze NADPH oxidation and the following nanozyme catalytic cascade reactions to produce hydroxyl radicals and prevent GSH regeneration, thus promoting the ferroptotic death of cancer cells. Briefly, the Pt-MIL-101 nanomedicine possessing NADPH oxidase (NOX)-like activity catalyzes the superoxide anions (O₂^•−) generation by promoting the electron transfer from NADPH to O₂, followed by Pt-MIL-101-catalyzed O₂^•− disproportionation producing H₂O₂ using its superoxide dismutase (SOD) nanozyme catalytic activity. The generated H₂O₂ further serves as substrate for toxic ∙OH production via Fenton reaction with Fe³⁺/Fe²⁺ at the structure center of the MIL-101. Moreover, the NOX nanozyme-catalyzed NADPH depletion by the nanomedicine largely prevents the GSH regeneration and de-activates GPX4, promoting lipid peroxidation for ferroptotic cell death. This work highlights an effective NADPH-initiated nanozyme cascade nanocatalytic strategy for ferroptosis-based tumor therapy.