具有超高原子利用效率的单原子纳米酶（SAzymes）已广泛应用于活性氧（ROS）介导的癌症治疗。然而，反应中间体单原子位点的高能垒以及肿瘤微环境中过度表达的抗氧化剂限制了肿瘤氧化应激的放大，导致治疗效果不理想。在此，我们报道了一种具有多种催化活性位点的多酶模拟MoCu双原子纳米酶（MoCu DAzyme），其表现出过氧化物酶、氧化酶、谷胱甘肽（GSH）氧化酶和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶模拟活性。与Mo SAzyme相比，Cu原子的引入、双原子位点的形成以及各个活性位点之间的协同催化作用增强了底物的吸附并降低了能垒，从而赋予了MoCu DAzyme更强的催化活性。受益于上述类酶活性，MoCu DAzyme不仅可以产生多种ROS，还可以消耗GSH并阻止其再生，从而触发氧化应激的级联放大。此外，近红外II生物窗口的强光吸收赋予MoCu DAzyme卓越的光热转换性能。因此，MoCu DAzyme 实现了结合协同催化疗法和光热疗法的高效协同癌症治疗。这项工作将推进 DAzyme 的治疗应用，并为纳米催化癌症治疗提供宝贵的见解。© 2024 Wiley‐VCH GmbH。

Single-atom nanozymes (SAzymes) with ultrahigh atom utilization efficiency have been extensively applied in reactive oxygen species (ROS)-mediated cancer therapy. However, the high energy barriers of reaction intermediates on single-atom sites and the overexpressed antioxidants in the tumor microenvironment restrict the amplification of tumor oxidative stress, resulting in unsatisfactory therapeutic efficacy. Herein, we report a multi-enzyme mimetic MoCu dual-atom nanozyme (MoCu DAzyme) with various catalytic active sites, which exhibits peroxidase, oxidase, glutathione (GSH) oxidase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mimicking activities. Compared with Mo SAzyme, the introduction of Cu atoms, formation of dual-atom sites, and synergetic catalytic effects among various active sites enhance substrate adsorption and reduce the energy barrier, thereby endowing MoCu DAzyme with stronger catalytic activities. Benefiting from the above enzyme-like activities, MoCu DAzyme can not only generate multiple ROS, but also deplete GSH and block its regeneration to trigger the cascade amplification of oxidative stress. Additionally, the strong optical absorption in the near-infrared II bio-window endows MoCu DAzyme with remarkable photothermal conversion performance. Consequently, MoCu DAzyme achieves high-efficiency synergistic cancer treatment incorporating collaborative catalytic therapy and photothermal therapy. This work will advance the therapeutic applications of DAzymes and provide valuable insights for nanocatalytic cancer therapy.© 2024 Wiley‐VCH GmbH.