Self-Amplifying Cascade Enzymatic Nanoplatform Orchestrating Metabolic Reprogramming and Oxidative Stress for Antitumor Therapy

Abstract

Nanocatalytic tumor therapy utilizes nanomaterials to catalyze chemical reactions, producing cytotoxic species that kill tumor cells; however, the metabolic heterogeneity of tumor cells significantly compromises therapeutic efficacy. Herein, we developed a self-amplifying cascade enzymatic nanoplatform (ReS₂@GOx) for nanocatalytic tumor therapy by orchestrating metabolic reprogramming and oxidative stress. This nanoplatform integrates rhenium disulfide (ReS₂) nanozyme possessing trimodal enzyme-mimetic activities (catalase (CAT)-like, nicotinamide adenine dinucleotide (NADH) oxidase (NOX)-like, and glutathione oxidase (GSHOx)-like activities) with glucose oxidase (GOx), enabling three interlocked therapeutic actions: (1) external energy-independent singlet oxygen (¹O₂) generation through ReS₂-mediated hydrogen peroxide (H₂O₂) conversion involving a superoxide anion (•O₂^-) intermediate; (2) attenuation of metabolic circuits through NADH oxidation and glutathione depletion; and (3) a cyclic cascade reaction driven by GOx-mediated glucose oxidation and H₂O₂ production, coupled with CAT-mediated H₂O₂-to-O₂ conversion, sustaining glucose oxidation and NADH consumption. Mechanistic studies reveal a noncanonical ¹O₂ generation pathway involving electron shuttle-mediated •O₂^– conversion, establishing a redox loop fueled by endogenous substrates (e.g., glucose, NADH). The coordinated enzymatic triad achieves dual tumor suppression, including blocking adenosine triphosphate (ATP) production by inhibiting glycolysis/oxidative phosphorylation (OXPHOS) and inducing lipid peroxidation. This work demonstrates a nanocatalytic tumor therapy strategy that orchestrates tumor metabolism to potentiate oxidative lethality, highlighting the therapeutic potential of metabolic regulation for tumor treatment.