Biomimetic nanoplatform with H₂O₂ 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 (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 (CAT) and depleting intracellular GSH, resulting in disrupted H₂O₂ homeostasis in tumor. Moreover, the elevated H₂O₂ will transform into highly toxic hydroxyl radical (·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 H₂O₂ level and antioxidant defense system in tumor tissues significantly impair the therapeutic effect of CDT. Herein, we developed an intelligent nanoplatform with H₂O₂ 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 H₂O₂, while the suppression of CAT activity by 3AT and depletion of GSH by Cu²⁺ would weaken the antioxidant defense system of tumors. Ultimately, the raised H₂O₂ level would convert to highly toxic •OH by Fenton-like reaction, amplifying the CDT efficacy. This work provides a promising strategy for cancer management.