Antioxidant hydrogel enriched with Pyk2 exosomes accelerates diabetic wound healing via synergistic immunomodulation and angiogenesis

The recalcitrance of diabetic wounds is primarily driven by a hostile microenvironment characterized by oxidative stress and impaired tissue regeneration. To address these impediments, we engineered an integrated Carrier-Cargo therapeutic strategy. Initial comparative screening revealed that exosomes derived from human umbilical cord mesenchymal stem cells (UCMSCs), termed UCMSC-Exo, exhibited superior endothelial modulatory capabilities compared with those derived from adipose-derived mesenchymal stem cells (ADSCs) or dermal mesenchymal stem cells (DMSCs). To ensure sustained bioactivity, an antioxidant, thermosensitive poly(citrate-gallic acid) hydrogel (FPGEGa) was developed as the delivery vehicle. Quantitative proteomics further identified proline-rich tyrosine kinase 2 (Pyk2) as the critical functional cargo enriched in UCMSC-Exo. Mechanistically, the FPGEGa hydrogel scavenges pathological reactive oxygen species (ROS) to ameliorate the oxidative microenvironment. Concurrently, Pyk2-enriched UCMSC-Exo facilitate macrophage polarization toward the M2 phenotype and enhance angiogenesis. Crucially, the therapeutic benefits were significantly attenuated in wounds treated with Pyk2-depleted exosomes, resulting in persistent inflammation and reduced neovascularization. This finding confirms Pyk2 as an indispensable mediator of therapeutic efficacy. Collectively, this study establishes a synergistic strategy in which the hydrogel restores redox homeostasis, creating a favorable niche for exosome to exert its immunomodulatory and pro-angiogenic effects, thereby offering a potent cell-free therapy for accelerating diabetic wound repair.