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

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

  • J Colloid Interface Sci. 2025 Sep 25;703(Pt 1):139108. doi: 10.1016/j.jcis.2025.139108.
Jiaxin Lin 1,  Jingqi Chen 1,  Minghao Li 2,  Dan Li 1,  Zheye Zhang 3,  Peng Chen 4,  Weiqing Zhang 5
Affiliations

Affiliations

  • 1 Department of Experimental Research, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Guangxi 530021, China.
  • 2 Department of Medical Imaging Center, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Guangxi 530021, China.
  • 3 School of Chemistry, Chemical Engineering and Biotechnology, Lee Kong Chian School of Medicine, Institute for Digital Molecular Analytics and Science, Nanyang Technological University, Singapore 637459, Singapore.
  • 4 School of Chemistry, Chemical Engineering and Biotechnology, Lee Kong Chian School of Medicine, Institute for Digital Molecular Analytics and Science, Nanyang Technological University, Singapore 637459, Singapore. Electronic address: chenpeng@ntu.edu.sg.
  • 5 Department of Experimental Research, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Extremely Weak Magnetic Field in Cancer Medicine, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Guangxi 530021, China. Electronic address: zhangweiqing@tjut.edu.cn.
PMID: 41045899 DOI: 10.1016/j.jcis.2025.139108
Abstract

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.

Keywords

Mitochondrial dysfunction; PANoptosis; Reactive oxygen species; Redox-mediated cancer therapy; Single-atom nanozymes.

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