Pyk2外泌体抗氧化水凝胶通过免疫调节和血管生成促进糖尿病伤口愈合研究

Abstract

A stimuli-responsive antioxidant hydrogel neutralizes oxidative stress and delivers therapeutic extracellular vesicles. • A specific tyrosine kinase within the vesicles as the core molecular driver of tissue regeneration. • The hydrogel restores redox balance, enabling the kinase to drive immunomodulation and new vessel formation. • Kinase depletion attenuates efficacy, validating the synergistic material-biology mechanism for diabetic wounds. 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