Tripartite Cascading Functions of Ultrathin RhMo Nanozymes in Tumor Catalytic Therapy

ABSTRACT Nanozymes with photothermal regulation capabilities facilitate spatiotemporally controlled tumor therapy. However, the generated heat stress inevitably upregulates heat shock protein 90 (HSP90), which induces thermotolerance and compromises therapeutic efficacy. To resolve this dilemma, we developed ultrathin metallic RhMo (RM) nanosheets integrating tripartite cascading functions with flexoelectric catalytic, photothermal, and multi‐enzyme properties. Accordingly, a “metabolic regulation‐synergistic killing” strategy is proposed. Initially, ultrasound‐driven flexoelectric catalysis was used as a metabolic pretreatment. By oxidizing intracellular nicotinamide adenine dinucleotide hydride (NADH) to nicotinamide adenine dinucleotide (NAD + ), it severs the substrate supply for the tricarboxylic acid cycle. The consequent depletion of intracellular adenosine triphosphate (ATP) fundamentally inhibits ATP‐dependent HSP90 activity, thereby abrogating the thermal defense of tumors. Subsequently, under near‐infrared irradiation, RM generates localized hyperthermia, which amplifies its intrinsic peroxidase‐, oxidase‐, and catalase‐like activities. These activities trigger a massive burst of reactive oxygen species (ROS) from endogenous substrates. The convergence of ATP deprivation and ROS‐related oxidative stress induces severe mitochondrial damage and cytochrome C release, leading to irreversible apoptosis. This study established a controllable chemotherapy‐free paradigm that leverages flexoelectric metabolic interventions to overcome thermotolerance for efficient tumor catalytic therapy.