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Adhesive polyethylene glycol hydrogels with metformin enabling in-situ drug delivery reprogramming immuno-metabolism for tissue repair in diabetic foot ulcers
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DOI：10.1016/j.actbio.2026.04.033.png)
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Abstract
En 中文
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 volume 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 spectrum 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.
Keywords:
PEG hydrogel
metformin
diabetic foot ulcer
macrophage polarization
immuno-metabolism
Journal
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9.6
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Citations:
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