<p>The wounds of diabetic patients are prone to bacterial infection due to complex microenvironments. Improving the microenvironment of diabetic wounds and controlling bacterial infection are crucial for wound healing in diabetic patients. We constructed a cascade catalytic antibacterial agent (<i>h</i>-CuSe-PEG/GOx) by using the hollow copper selenide nanocubes (<i>h</i>-CuSe NCs) loaded with glucose oxidase (GOx). The sythesized <i>h</i>-CuSe NCs possess peroxidase-like (POD-like), glutathione peroxidase-like (GPx-like), and oxidase-like (OXD-like) activities. The loaded GOx can reduce the wound pH and generate H₂O₂ in situ, further enhancing the catalytic reactive oxygen species (ROS) generation. The <i>h</i>-CuSe-PEG/GOx exhibited efficient antimicrobial properties against Gram-negative Escherichia coli (<i>E. coli</i>), Gram-positive Staphylococcus aureus (<i>S. aureus</i>), as well as ampicillin-resistant Escherichia coli (MREC) and methicillin-resistant Staphylococcus aureus (MRSA). The results of in vivo experiments showed that <i>h</i>-CuSe-PEG/GOx reduced the expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) by inhibiting bacterial growth, thereby alleviating the inflammatory response. At the same time, it enhanced the expression of cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF) and promoted angiogenesis. Therefore, the use of cascade catalytic nanozyme strategy can effectively control bacterial infection, improve wound microenvironment and promote wound healing, which is of clinical significance for the treatment of diabetic wounds.</p> Graphical abstract <p></p>