Redox-engineered gold single-atom nanozymes orchestrate mitochondria-driven PANoptosis for energy-independent cancer catalytic therapy

Reactive Oxygen Species (ROS) are central regulators of redox homeostasis and cell fate. However, their precise orchestration to trigger PANoptosis, a coordinated form of programmed cell death (PCD) integrating Pyroptosis, Apoptosis, and Necroptosis, remains underexplored. Herein, we report a gold single-atom nanozyme (Au-SA/NHC) featuring atomically dispersed AuN₄ sites that enable energy-independent, parallel and cascaded ROS generation. By mimicking peroxidase (POD), catalase (CAT), and glutathione oxidase (GSH-OXD) activities, Au-SA/NHC sustainably produces singlet oxygen (¹O₂) and hydroxyl radicals (∙OH) from endogenous substrates while depleting glutathione (GSH) to amplify oxidative stress. This redox remodeling triggers mitochondrial dysfunction, which acts as a central hub to bridge ROS stress with the assembly of the PANoptosome and activation of downstream signaling. Pharmacological and redox interventions-including ROS scavenging, mitochondrial protection, and inhibition of individual death modules-validated this axis and confirmed that PANoptosis represents the predominant cell death mode induced by Au-SA/NHC. In vivo, Au-SA/NHC significantly suppressed tumor growth with favorable biocompatibility, whereas ROS scavenging abolished therapeutic efficacy, underscoring the essential role of oxidative stress. Collectively, this work establishes a redox-engineered single-atom nanozyme as a next-generation catalytic nanotherapy capable of precisely engaging coordinated cell death programs through the ROS-mitochondria-PANoptosis axis.