Baicalein based nano-delivery system restores mitochondrial homeostasis through PPAR signaling pathway to promote wound healing in diabetes

Wound healing in diabetes is a substantial clinical challenge due to the hyperglycemic microenvironment, high pH, bacterial infection, persistent inflammation, and impaired cellular functions, attributed to mitochondrial dysfunction. Here, we have developed an injectable photo-crosslinking nanocomposite hydrogel (BA/GOx@ZIF-8@GelMA, BGZ@GelMA) with baicalein (BA) and glucose oxidase (GOx) loaded Zinc metal-organic framework (ZIF-8) based on methacrylated gelatin (GelMA) to accelerate diabetic infected wound healing by regulating subcellular and cellular functions. The combination of ZIF-8 and BA gives the hydrogel excellent antibacterial properties. A high blood sugar environment triggers the release of GOx in BGZ@GelMA, reducing local glucose and pH, producing hydrogen peroxide (H₂O₂), and releasing BA and Zinc ions (Zn²⁺). This process provides a suitable microenvironment for wound healing. Zn²⁺ can significantly inhibit the proliferation of Staphylococcus aureus (S.aureus) and Escherichia coli (E.coli). The released BA can clear ROS in cells and mitochondria, restore mitochondrial function and stability, and make the hydrogel fundamentally improve the cell function damage induced by hyperglycemia, and ultimately promote cell proliferation, migration and angiogenesis. In general, our multifunctional nanocomposite hydrogel provides a new strategy for diabetes wound healing at the subcellular and cellular functional levels.