Bifunctional KatG‐Mimic Activity of Nanosheet for Coupled Catalytic Therapy of Hypoxic Tumor

Abstract In contrast to the single‐functional enzymes such as superoxide dismutase and catalase, catalase‐peroxidase (KatG) is a special natural enzyme with bifunctional activity that catalyzes the decomposition of hydrogen peroxide (H ₂ O ₂ ) into both oxygen (O ₂ ) and radicals. Inspired by the unique catalytic activity of KatG, this study synthesized a two‐dimensional (2D) tannic copper (CuTA) nanosheet with KatG‐like catalytic activity, which is used for enhanced nanocatalytic tumor therapy by hypoxic modulations. CuTA presents a mixed‐valence catalytic center (Cu ²⁺ /Cu ⁺ ) through the stable coordination of copper ions with tannic acid, which endows the catalyst with exceptional electron transfer capabilities and dynamic redox cycling properties, thus providing excellent peroxidase‐like activity to generate hydroxyl radicals (•OH) ( K _m = 18.8 µ m , V _max = 3.83 × 10 ⁻⁸ m ·s ⁻¹ ), and catalase‐like activity to generate O ₂ ( K _m = 96.95 m m , V _max = 12.37 × 10 ⁻⁷ m ·s ⁻¹ ). Cell experiments demonstrate that catalytic O ₂ generation by CuTA alleviates the tumor hypoxia and therefore sensitizes cancer cells to the oxidative attack by catalytically generated •OH. In vivo experiments further confirm the significant antitumor efficacy of CuTA. This study highlights the promising potential of the KatG‐mimic nanocatalyst in hypoxic modulation and hypoxic tumor treatment through coupled catalytic regulations.