Multifunctional metal organic framework-based hydrogel for accelerating diabetic wound healing

Chronic diabetic wound remains a major clinical challenge due to its persistent inflammation, oxidative stress, impaired angiogenesis, and delayed re-epithelialization. Here, a miR-21-5p-loaded bimetallic metal-organic framework (RMOF) was constructed using magnesium and zinc as metal clusters, while utilizing gallic acid and indole-3-propionic acid as mixed organic ligands, enabling synergistic antioxidant, anti-inflammatory, and immunomodulatory properties besides multiple bioactivities brought by miR-21-5p. Subsequently, we developed a multifunctional in-situ forming hydrogel dressing by embedding RMOF into a polyethylene glycol (PEG) matrix that exhibits skin-like mechanical properties and sustained release behavior. In vitro studies demonstrated that RMOF significantly promoted proliferation, migration, and tube formation of relevant cells, while also inducing M2 polarization of macrophages and neuronal differentiation of neural stem cells. In a diabetic rat full-thickness skin wound model, PEG-RMOF treatment markedly accelerated wound closure at about 62.3% after 10 days, enhanced collagen deposition significantly, reduced oxidative stress among the entire wound, and increased the expression of key regenerative markers, especially about Nestin and β-Catenin compared to PEG-miR group. In addition, RMOF effectively retained both miR-21-5p and metal ions abundance in wound tissues. Collectively, our research presents a versatile MOF-based hydrogel platform that integrates multiple bioactive components to coordinately promote diabetic wound healing, offering a promising strategy for chronic wound management.