Adhesive polyethylene glycol hydrogels with metformin enabling in-situ drug delivery reprogramming immuno-metabolism for tissue repair in diabetic foot ulcers

Diabetic foot ulcer (DFU) is characterized by persistent inflammation, metabolic dysfunction, and impaired angiogenesis, leading to refractory chronic wounds. Here, we report an adhesive, metformin-loaded (1.0 mM) polyethylene glycol (PEG) based hydrogel (i.e., PEG/Met), constructed from equal volumes of PEG-SG (20 wt.%) and PEG-NH₂ (20 wt.%), to regulate macrophage polarization and metabolism in DFU. Density functional theory (DFT) calculations and infrared spectra confirmed its crosslinking, yielding a homogeneous PEG network with strong tissue adhesion (31.4 ± 8.6 kPa) and sustained drug release till seven days (total release: 86.8 ± 0.6%). In a rat DFU model, the PEG/Met significantly accelerated wound closure (wound recovery: 91.9 ± 3.4%, which was 1.96-fold to the control), collagen deposition, M2-like macrophage infiltration, and neovascularization. Under lipopolysaccharides (LPS) or Staphylococcal protein A (SpA) induced pro-inflammatory stimulation, the PEG/Met suppressed glycolytic flux, reduced glucose uptake and consumption, yet increased adenosine triphosphate (ATP) production and restored oxygen consumption, indicating a shift from glycolysis toward oxidative phosphorylation (OXPHOS). Likewise, the PEG/Met restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, increased Egln3 expression, and decreased Hif-1α and IL-1β levels, thereby alleviating Hif-1α-driven inflammatory signaling. Pharmacologic inhibition of OXPHOS with rotenone reversed PEG/Met-induced M2 polarization and reactivated pro-inflammatory gene expression, confirming the intact mitochondrial respiration for its immunoregulatory effects. This PEG/Met hydrogel functioned as both an adhesive, drug-delivery platform and immune-metabolic modulator, effectively reprogramming macrophage phenotype and mitochondrial metabolism, which held substantial promise as a localized therapy for DFU and other chronic wounds. STATEMENT OF SIGNIFICANCE: Diabetic foot ulcer (DFU) is a leading cause of limb loss worldwide, as traditional dressings only passively cover wounds without resolving chronic inflammation caused by metabolic and immune disorders. Here, we fabricated a polyethylene glycol (PEG) based adhesive hydrogel for local metformin delivery (PEG/Met), which achieved strong tissue adhesion, biodegradability, and sustained drug release. The hydrogel reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, thereby improving mitochondrial function, decreasing mitochondrial reactive oxygen species, enhancing Egln3-mediated Hif-1α ubiquitination, and alleviating IL-1β-mediated inflammation. This hydrogel created a pro-angiogenic microenvironment to accelerate DFU healing in vivo. By linking the clinically approved metformin, this adhesive hydrogel platform offered a translational strategy for treating DFU and other chronic wounds.