A MMP9-responsive nanozyme hydrogel to promote diabetic wound healing by reconstructing the balance of pro-inflammation and anti-inflammation

Excessive reactive oxygen species (ROS) lead to persistent inflammation in diabetic wounds inducing excessive inflammatory factors and matrix metalloproteinases (MMPs), thereby hindering wound healing. However, low concentration ROS also function as a signaling molecule for maintaining cell function and promoting vascularization. Therefore, it is important to regulate ROS levels adaptively to match the healing process. Here, a nanozyme hydrogel was developed to intelligently clear wound ROS in response to dynamic changes of matrix metalloproteinase-9 (MMP9). Specifically, Prussian blue nanoparticle (PBNP) loaded-gelatin nanospheres (PGs) were encapsulated in polyvinyl alcohol (PVA) hydrogel to obtain a nanozyme hydrogel (PGs@PVA). Hydrogen bonding between PGs and PVA not only improves the mechanical properties of the PGs@PVA hydrogel but also ensures the controlled release of PBNPs. With the release of PBNP from the PGs@PVA hydrogel in response to the high level of MMP9 in the pro-inflammatory stage, excessive ROS were cleared. The phenotype of the macrophages was regulated correspondingly. The <i>in vivo</i> results proved that the PGs@PVA hydrogel promoted healing speed, epithelialization, vascularization, and collagen deposition of diabetic wounds by adaptive immunomodulation. The MMP9-responsive nanozyme hydrogel shows great potential in diabetic wound healing by reconstructing the balance of pro-inflammation and anti-inflammation.