Engineering biomimetic ATP-responsive Se-containing core-shell cascade nanozyme for efficient tumor combination therapy

Composite nanocatalysts combined with natural GOx and Se-containing core-shell biomimetic cascade nanozymes were developed for efficient cancer chemodynamic therapy. • Selenium enzyme assembled core-shell structure biochemical reactors by coordination bonds. • Accelerated intratumoral GSH depletion under selenium enzyme catalysis to destroy intratumoral redox protection mechanisms. • Natural enzymes and artificial enzymes synergistically enhanced CDT efficacy. The ineffectiveness of cancer chemodynamic treatment (CDT) is intimately connected to intracellular antioxidant defense mechanisms. While great efforts have been made to interfere with the oxidative protection mechanisms within tumor cells, this remains a difficult challenge. Herein, inspired by the glutathione peroxidase (GPx) function for consuming GSH, an artificial selenase was designed to combine with the Fenton reaction to prepare a metal complex nanocarrier (IM-Se-Ph@TA-Fe NPs), in which glucose oxidase (GOx) is loaded to obtain the multienzyme synergic nanozyme GOx@IM-Se-Ph@TA-Fe NPs. In response to the high expression of ATP in the tumor, released GOx could specifically reduce the molecular oxygen to H 2 O 2 by consuming intratumoral glucose and cause tumor starvation. Following that, the generated H 2 O 2 supported the intracellular Fenton reaction and consumed intracellular GSH under the catalysis of selenase to enhance multimodal cancer therapy. The strategy of interfering with the intracellular antioxidant system by utilizing artificial selenase and GOx increases the efficacy of chemodynamic therapy and offers new concepts for cancer combination therapy.