One-Pot Rapid Synthesis of Cu2+-Doped GOD@MOF to Amplify the Antitumor Efficacy of Chemodynamic Therapy

Chemodynamic therapy (CDT) relies on the transformation of intracellular hydrogen peroxide (H₂O₂) to hydroxyl radicals (·OH) with higher toxicity under the catalysis of Fenton/Fenton-like reagents, which amplifies the oxidative stress and induces significant cellular apoptosis. However, the CDT efficacy is generally limited by the overexpressed GSH and insufficient endogenous H₂O₂ in tumors. Co-delivery of Cu²⁺ and glucose oxidase (GOD) can lead to a Cu²⁺/Cu⁺ circulation to realize GSH depletion and amplify the Fenton-like reaction. pH-responsive metal-organic frameworks (MOFs) are the optical choice to deliver Fenton/Fenton-like ions to tumors. However, considering that the aqueous condition is requisite for GOD encapsulation, it is challenging to abundantly dope Cu²⁺ in ZIF-8 MOF nanoparticles in aqueous conditions due to the ease of precipitation and enlarged crystal size. In this work, a robust one-pot biomimetic mineralization method using excessive ligand precursors in aqueous conditions is developed to synthesize GOD@Cu-ZIF-8. Copper ions abundantly doped to the GOD@Cu-ZIF-8 can eliminate GSH to produce Cu⁺, which is further proceeded to the Fenton-like reaction in the presence of GOD-catalyzed H₂O₂. Through breaking the tumor microenvironment homeostasis and producing an enhanced CDT effect, the promising antitumor capability of GOD@Cu-ZIF-8 was evidenced by the experiments both in vitro and in vivo.