High-Performance\nSelf-Cascade Pyrite Nanozymes for\nApoptosis–Ferroptosis Synergistic Tumor Therapy

As\nnext-generation artificial enzymes, nanozymes have shown great\npromise for tumor catalytic therapy. In particular, their peroxidase-like\nactivity has been employed to catalyze hydrogen peroxide (H₂O₂) to produce highly toxic hydroxyl radicals (^•OH) to kill tumor cells. However, limited by the low affinity between\nnanozymes with H₂O₂ and the low level of H₂O₂ in the tumor microenvironment, peroxidase nanozymes\nusually produced insufficient ^•OH to kill tumor\ncells for therapeutic purposes. Herein, we present a pyrite peroxidase\nnanozyme with ultrahigh H₂O₂ affinity, resulting\nin a 4144- and 3086-fold increase of catalytic activity compared with\nthat of classical Fe₃O₄ nanozyme and natural\nhorseradish peroxidase, respectively. We found that the pyrite nanozyme\nalso possesses intrinsic glutathione oxidase-like activity, which\ncatalyzes the oxidation of reduced glutathione accompanied by H₂O₂ generation. Thus, the dual-activity pyrite nanozyme\nconstitutes a self-cascade platform to generate abundant ^•OH and deplete reduced glutathione, which induces apoptosis as well\nas ferroptosis of tumor cells. Consequently, it killed apoptosis-resistant\ntumor cells harboring KRAS mutation by inducing ferroptosis. The pyrite\nnanozyme also exhibited favorable tumor-specific cytotoxicity and\nbiodegradability to ensure its biosafety. These results indicate that\nthe high-performance pyrite nanozyme is an effective therapeutic reagent\nand may aid the development of nanozyme-based tumor catalytic therapy.