Although nanocatalytic therapy has become an emerging strategy for tumor treatment, the therapeutic effects of reactive oxygen species (ROS)-mediated treatment are still seriously limited by the inherent flaws of the enzymatic activities and the specific physicochemical properties of the tumor microenvironment (TME). Herein, we report an ultrasmall bimetallic oxide nanozyme (CuFe₂O₄@PEG, CFOs) for programmable multienzyme-like activities-primed combined therapy. Under the acidic condition, abundant highly toxic ROS can be generated through the peroxidase activity of CFOs with overexpressed hydrogen peroxide (H₂O₂) in the tumor. High metal ion utilization of bimetallic oxide nanozymes is related to the size effect and topological structure. Furthermore, glutathione peroxidase activity-initiated depletion of GSH disrupts the intracellular antioxidant defense system and further amplifies the oxidative stress in turn. Subsequently, oxygen generation originating from the catalase activity of CFOs relieves tumor hypoxia and achieves exceptional TME-customized therapeutic effects. Notably, the high photothermal effect (η = 41.12%) of CFOs in the second near-infrared biological windows leads to the combinational inhibition of tumor growth. In summary, this report provides a paradigm for the rational design of TME-responsive and ROS-mediated nanocatalytic treatment, which is promising for achieving superior therapeutic efficiency.

尽管纳米催化疗法已成为一种新兴的肿瘤治疗策略，但活性氧（ROS）介导的治疗效果仍然受到酶活性的固有缺陷和肿瘤微环境（TME）的特定理化性质的严重限制。在此，我们报告了一种超小型双金属氧化物纳米酶（CuFe ₂ O ₄ @PEG，CFOs），用于可编程多酶类活动引发的联合治疗。在酸性条件下，过氧化氢（H ₂ O ₂) 在肿瘤中。双金属氧化物纳米酶的高金属离子利用率与尺寸效应和拓扑结构有关。此外，谷胱甘肽过氧化物酶活性引发的 GSH 消耗破坏了细胞内的抗氧化防御系统，进而进一步放大了氧化应激。随后，源自 CFO 的过氧化氢酶活性的氧气生成缓解了肿瘤缺氧并实现了卓越的 TME 定制治疗效果。值得注意的是，高光热效应（η = 41.12%) 第二近红外生物窗中的 CFO 导致肿瘤生长的组合抑制。总之，本报告为合理设计 TME 响应和 ROS 介导的纳米催化治疗提供了范例，有望实现卓越的治疗效率。