Polyphenol‐Copper Derived Self‐Cascade Nanozyme Hydrogel in Boosting Oxygenation and Robust Revascularization for Tissue Regeneration

Abstract The regeneration of hypoxia‐impaired chronic tissue defects has long been challenging, mainly due to the inefficiency of oxygenation and the limited biological activity of existing oxygen delivery systems in regulating dynamic tissue regeneration process. Herein, a novel polyphenol‐copper coordination strategy to fabricate bioactive superoxide dismutase‐catalase self‐cascade nanozymes (SalB‐CuNCs) is reported, which can serve as an in situ oxygenator and induce angiogenesis simultaneously. The copper‐phenolic hydroxyl coordination structure in SalB‐CuNCs plays a critical role in promoting the enzyme‐like cascade reaction via catechol‐mediated Cu valence state transition and substrate capture mechanism. Furthermore, after incorporating SalB‐CuNCs into a Schiff base hydrogel (COC@SalB‐Cu), the resulting system exhibits outstanding antioxidant and robust oxygenation effect in mitigating the hypoxic microenvironment. Benefiting from the intrinsic angiogenic activity of SalB and copper, COC@SalB‐Cu hydrogel can induce a more complete tube formation by up‐regulating the expression level of vascular endothelial growth factor (VEGF), platelet‐endothelial cell adhesion molecule‐1 (CD31), and endothelial nitric oxide synthase (eNOS). In vivo experiments further demonstrate that the COC@SalB‐Cu hydrogel can significantly restore the oxygen and blood supply, leading to fast tissue regeneration. The present strategy holds enormous promise for the treatment of hypoxia‐related chronic tissue defects and vascular injury in the field of regenerative medicine.