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 Au N 4 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 ( 1 O 2 ) 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.