Immunomodulatory microneedles restore mitochondrial homeostasis and balance TGF-β/TNF-α signaling to accelerate diabetic wound repair

s Diabetic infected wounds bring great physical and psychological burden to patients. To solve this problem, removing bacteria and regulating the local immune microenvironment have become effective measures. However, traditional wound repair materials are difficult to break through the bacterial biofilm covering the wound site and thus cannot effectively regulate the internal immune environment of the wound. A bilayer multifunctional sulfonated chitosan (SCS)/ methacrylated hyaluronic acid (HAMA)/ methacrylated collagen III (Col III MA) (SCS/HAMA/Col III MA, SHC) microneedle loaded with MXene@Zn-MOF (MXZ) composite was designed for diabetic infected wound repair. The MXZ composite achieved more than 99% bacterial inhibition against both E. coli and S. aureus , and was able to effectively remove the bacterial biofilm. In addition, SHC + MXZ microneedles were able to promote angiogenesis by activating the Transforming Growth Factor-β (TGF-β) signaling pathway. It also regulated macrophage polarization towards the M2 phenotype and inhibited the Tumor Necrosis Factor-α (TNF-α) signaling pathway to reduce the level of inflammation. Further studies on mitochondrial membrane potential showed that SHC + MXZ microneedles were able to restore the decrease in mitochondrial membrane potential caused by ROS and then restore mitochondrial function. In diabetic infected wound repair results showed that SHC + MXZ microneedles effectively promoted diabetic infected wound repair by promoting angiogenesis and reducing the inflammation level of the wound tissue.Finally, the regulation of related gene expression was explored by transcriptome sequencing, and the intrinsic mechanism of SHC MXZ microneedles in promoting the repair of diabetic infected wounds by regulating the TGF-β and TNF-α signaling pathways was elucidated.