化学动力疗法（CDT）是一种强大的癌症治疗策略，通过产生过量的活性氧（ROS）来杀死癌细胞。然而，肿瘤组织中氢过氧化物（H2O2）供应不足和抗氧化防御系统显著削弱了CDT的治疗效果，阻碍了它的进一步应用。因此，我们提出了一种具有H2O2稳态破坏和氧化应激放大特性的智能纳米平台，以增强CDT的疗效。该纳米平台由pH和谷胱甘肽（GSH）响应性可降解的铜掺杂沸石咪唑骨架（Cu-ZIF8）囊括葡萄糖氧化酶（GOx）而成，随后通过装载3-氨基-1,2,4-三唑（3AT）和修饰透明质酸（HA）进行肿瘤靶向递送。GOx@Cu-ZIF8-3AT@HA不仅通过耗尽肿瘤内部的葡萄糖来减少能量供应和增加H2O2水平，还通过抑制过氧化氢酶的活性和耗尽细胞内的GSH来扰乱肿瘤的抗氧化防御系统，从而打破肿瘤内的H2O2稳态。此外，H2O2通过Cu2+生成的氧化还原反应会转化为高毒性的•OH，从而增强氧化应激作用，提高CDT的疗效。最终，经过测试，GOx@Cu-ZIF8-3AT@HA显著抑制了4T1移植瘤的生长，没有明显的副作用，为癌症管理提供了一种有前途的策略。这项工作具有重要意义：肿瘤组织中H2O2水平不足和抗氧化防御系统显著削弱了CDT的疗效。我们开发了一种具有H2O2稳态破坏和氧化应激放大特性的智能纳米平台，通过使用GOx耗尽肿瘤内部的葡萄糖减少能量供应，并增加H2O2的产生，同时使用3AT抑制过氧化氢酶的活性并耗尽GSH削弱肿瘤的抗氧化防御系统，最终通过Fenton-like反应将提高的H2O2水平转化为高毒性的•OH进而增强CDT的疗效。这项研究为癌症管理提供了一种有前途的策略。版权所有 © 2023 Elsevier Ltd。

Chemodynamic therapy (CDT) is a powerful cancer treatment strategy by producing excessive amount of reactive oxygen species (ROS) to kill cancer cells. However, the inadequate hydrogen peroxide (H2O2) supply and antioxidant defense systems in tumor tissue significantly impair the therapeutic effect of CDT, hindering its further applications. Herein, we present an intelligent nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification properties for enhanced CDT. This nanoplatform is obtained by encapsulating glucose oxidase (GOx) in a pH- and glutathione (GSH)-responsive degradable copper doped-zeolitic imidazolate framework (Cu-ZIF8), followed by loading of 3-amino-1,2,4-triazole (3AT) and modification of hyaluronic acid (HA) for tumor targeting delivery. The GOx@Cu-ZIF8-3AT@HA not only reduces energy supply and increases H2O2 level by exhausting intratumoral glucose, but also disturbs tumor antioxidant defense systems by inhibiting the activity of catalase and depleting intracellular GSH, resulting in disrupted H2O2 homeostasis in tumor. Moreover, the elevated H2O2 will transform into highly toxic •OH by Cu+ that generated from redox reaction between Cu2+ and GSH, amplifying the oxidative stress to enhance the CDT efficacy. Consequently, GOx@Cu-ZIF8-3AT@HA has significantly inhibited the 4T1 xenograft tumor growth without discernible side effects, which provides a promising strategy for cancer management. STATEMENT OF SIGNIFICANCE: The inadequate hydrogen peroxide (H2O2) level and antioxidant defense system in tumor tissues significantly impair the therapeutic effect of chemodynamic therapy (CDT). Herein, we developed an intelligent nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification properties for enhanced CDT. In this nanoplatform, glucose oxidase (GOx) could exhaust intratumoral glucose to reduce energy supply accompanied with production of H2O2, while the suppression of catalase activity by 3-amino-1,2,4-triazole (3AT) and depletion of glutathione by Cu2+ would weaken the antioxidant defense system of tumors. Ultimately, the raised H2O2 level would convert to highly toxic hydroxyl radical (•OH) by Fenton-like reaction, amplifying the CDT efficacy. This work provides a promising strategy for cancer management.Copyright © 2023. Published by Elsevier Ltd.