Nanocatalytic Theranostics with Glutathione Depletion and Enhanced Reactive Oxygen Species Generation for Efficient Cancer Therapy

Abstract Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (•OH). To overcome the current limitations of the insufficient endogenous H2O2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC‐DOX) that possesses both H2O2 self‐supply and GSH‐elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one‐step biomineralization method using poly(ethylene glycol)‐modified glucose oxidase (GOx) as a template to form biodegradable copper‐doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H2O2, which not only starves the tumor cells, but also supplies H2O2 for subsequent Fenton‐like reaction. Meanwhile, the redox reaction between the released Cu2+ ions and intracellular GSH will induce GSH depletion and reduce Cu2+ to Fenton agent Cu+ ions, and then trigger the H2O2 to generate •OH by a Cu+‐mediated Fenton‐like reaction, resulting in enhanced CDT efficacy. The integration of GOx‐mediated starvation therapy, H2O2 self‐supply and GSH‐elimination enhanced CDT, and DOX‐induced chemotherapy, endow the PGC‐DOX with effective tumor growth inhibition with minimal side effects in vivo.