Biomimetic nanoplatform with HO homeostasis disruption and oxidative stress amplification for enhanced chemodynamic therapy.

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 (HO) 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 HO 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 HO level by exhausting intratumoral glucose, but also disturbs tumor antioxidant defense systems by inhibiting the activity of catalase (CAT) and depleting intracellular GSH, resulting in disrupted HO homeostasis in tumor. Moreover, the elevated HO will transform into highly toxic hydroxyl radical (·OH) by Cu that generated from redox reaction between Cu 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 HO level and antioxidant defense system in tumor tissues significantly impair the therapeutic effect of CDT. Herein, we developed an intelligent nanoplatform with HO homeostasis disruption and oxidative stress amplification properties for enhanced CDT. In this nanoplatform, GOx could exhaust intratumoral glucose to reduce energy supply accompanied with production of HO, while the suppression of CAT activity by 3AT and depletion of GSH by Cu would weaken the antioxidant defense system of tumors. Ultimately, the raised HO level would convert to highly toxic •OH by Fenton-like reaction, amplifying the CDT efficacy. This work provides a promising strategy for cancer management.