As next-generation artificial
enzymes, nanozymes have shown great promise for
tumor catalytic
therapy. In particular, their
peroxidase-like activity 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 nanozymes with H2O2 and the low level of H2O2 in the tumor microenvironment,
peroxidase nanozymes usually produced insufficient •OH to kill
tumor cells for therapeutic purposes. Herein, we present a
pyrite peroxidase nanozyme with ultrahigh H2O2 affinity, resulting in a 4144- and 3086-fold increase of catalytic activity compared with that of classical Fe3O4 nanozyme and natural
horseradish peroxidase, respectively. We found that the
pyrite nanozyme also possesses intrinsic
glutathione oxidase-like activity, which catalyzes the oxidation of
reduced glutathione accompanied by H2O2 generation. Thus, the dual-activity
pyrite nanozyme constitutes a self-cascade platform to generate abundant •OH and deplete
reduced glutathione, which induces apoptosis as well as ferroptosis of
tumor cells. Consequently, it killed apoptosis-resistant
tumor cells harboring KRAS mutation by inducing ferroptosis. The
pyrite nanozyme also exhibited favorable
tumor-specific cytotoxicity and biodegradability to ensure its biosafety. These results indicate that the high-performance
pyrite nanozyme is an effective therapeutic
reagent and may aid the development of nanozyme-based
tumor catalytic
therapy.