Antioxidant nanozyme-protected mesenchymal stem cells loaded on photo-crosslinked microsphere blocks for inflammatory deep tissue repair

Mesenchymal stem cells (MSCs) exhibit significant therapeutic potential in deep tissue repair due to their exceptional paracrine functions and immunomodulatory abilities. However, fabricating microsphere-based hydrogels that can simultaneously enhance MSC viability and retention in inflammatory wound microenvironments remain challenging. Herein, the MSC-encapsulated microsphere blocks incorporated with MnO₂@EGCG/Cu(II) (MEC) nanozymes are designed to relieve excessive oxidative stress and improve stem cell therapy in deep tissue repair. The MEC nanozymes exhibit enhanced biocompatibility, possess multiple enzymatic catalytic activities, and effectively protect MSCs from H₂O₂-induced oxidative damage. The GSM blocks, composed of methacryloyl gelatin and methacryloyl silk fibroin (GSM) microspheres, are further cross-linked using phenylboronic acid-modified methacryloyl gelatin (GelMA-PBA) and polyvinyl alcohol (PVA) (GP hydrogel) via dynamic covalent and permanent covalent bonds. The results of<em> in vivo</em> experiments reveal that the GP-GSM@MEC hydrogel not only adapts to irregular deep tissue wounds but also enhances the mechanical properties and tissue retention of GSM blocks through <em>in situ</em> photocrosslinking. Furthermore, GSM blocks significantly accelerated inflammatory deep tissue wound healing by alleviating excessive oxidative stress and tissue hypoxia, promoting tissue infiltration and vascularization. Therefore, this work provides an intelligent GSM block design strategy for MSC delivery, showing a promising alternative approach to improve the healing of inflammatory deep tissue defects.