A Versatile Nanozyme‐Based NADH Circulating Oxidation Reactor for Tumor Therapy through Triple Cellular Metabolism Disruption

Abstract Nanozyme‐based metabolic regulation triggered by tumor‐specific endogenous stimuli has emerged as a promising therapeutic strategy for tumors. The current efficacy, however, is constrained by the limited concentration of endogenous substrates and the metabolic plasticity of tumors. Consequently, the implementation of efficient metabolic regulation in tumor therapy is urgently needed. Herein, a versatile nanozyme‐based nicotinamide adenine dinucleotide (NADH) circulating oxidation nanoreactor is reported. First, the synthesized cobalt‐doped hollow carbon spheres (Co‐HCS) possess NADH oxidase (NOX)‐mimicking activity for the NADH oxidation to disrupt oxidative phosphorylation (OXPHOS) pathway of tumor cells. Second, the substrate‐cycle manner of Co‐HCS can be used for NADH circulating oxidation to overcome the limitation of substrate deficiency. Finally, 2‐Deoxy‐D‐glucose (2‐DG) and 6‐aminonicotinamide (6‐AN) are introduced to block glycolysis and pentose phosphate pathway (PPP), thus creating a versatile nanozyme‐based NADH circulating oxidation nanoreactor (Co‐HCS/D/A) for tumor therapy through triple cellular metabolism disruption. In vitro and in vivo results demonstrate that the designed nanoreactor not only enhances the catalytic efficiency but also disrupts the tumor metabolic homeostasis, leading to efficient therapy outcome. This study develops a novel NADH circulating oxidation nanoreactor for tumor therapy through triple cellular metabolism disruption, which addresses the limitations of current nanozyme‐based metabolism regulation for tumor therapy.