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<p>Chronic diabetic wounds are trapped in a persistent inflammatory state, largely due to macrophage failure to transition from pro-inflammatory (M1) to pro-reparative (M2) phenotypes. Here, we show that adipose-derived stem cell extracellular vesicles (ADSC-EVs) deliver functional mitochondria into diabetic wound macrophages, thereby restoring tricarboxylic acid (TCA) cycle-driven M2 polarization. Mechanistically, ADSC-EV-mediated mitochondrial transfer reactivates pyruvate dehydrogenase (<i>PDH</i>) and pyruvate carboxylase (<i>PC</i>), increases TCA cycle flux, and suggests enhanced glutamine anaplerosis, as evidenced by ¹³C-glucose isotope tracing. This metabolic rewiring restores oxidative phosphorylation (OXPHOS), elevates oxygen consumption rate (OCR) and suppresses glycolysis. Consequently, ADSC-EV treatment reduces M1 macrophages and increases M2 macrophages, lowers pro-inflammatory cytokines (<i>IL-1β</i>,<i> TNF-α</i>,<i> IL-6</i>,<i> MCP1</i>,<i> p</i> &lt; 0.0001), and upregulates <i>IL-10 in vitro</i>,<i> p</i> &lt; 0.0001). In a diabetic mouse wound model, a single course of ADSC-EVs accelerates wound closure at day 14 (<i>p</i> &lt; 0.05), enhances re-epithelialization and collagen deposition, and reduces local oxidative stress and inflammation. Mitochondria‑depleted Rho-ADSC-EVs show markedly diminished effects, confirming that functional mitochondrial transfer is the primary driver. Our findings establish ADSC-EV-mediated mitochondrial transfer as a central metabolic reprogramming strategy that breaks the inflammatory lock in diabetic wounds and promotes healing.</p> Graphical Abstract <p></p>

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Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Yue Zhang,
  • Fei Han,
  • Yixuan Yuan,
  • Mengyang Li,
  • Linbin Yi,
  • Yujie Xiao,
  • Dongliang Zhang,
  • Zhi Zhang,
  • Yunchuan Wang,
  • Hongtao Wang,
  • Dahai Hu

摘要

Chronic diabetic wounds are trapped in a persistent inflammatory state, largely due to macrophage failure to transition from pro-inflammatory (M1) to pro-reparative (M2) phenotypes. Here, we show that adipose-derived stem cell extracellular vesicles (ADSC-EVs) deliver functional mitochondria into diabetic wound macrophages, thereby restoring tricarboxylic acid (TCA) cycle-driven M2 polarization. Mechanistically, ADSC-EV-mediated mitochondrial transfer reactivates pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), increases TCA cycle flux, and suggests enhanced glutamine anaplerosis, as evidenced by ¹³C-glucose isotope tracing. This metabolic rewiring restores oxidative phosphorylation (OXPHOS), elevates oxygen consumption rate (OCR) and suppresses glycolysis. Consequently, ADSC-EV treatment reduces M1 macrophages and increases M2 macrophages, lowers pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, MCP1, p < 0.0001), and upregulates IL-10 in vitro, p < 0.0001). In a diabetic mouse wound model, a single course of ADSC-EVs accelerates wound closure at day 14 (p < 0.05), enhances re-epithelialization and collagen deposition, and reduces local oxidative stress and inflammation. Mitochondria‑depleted Rho-ADSC-EVs show markedly diminished effects, confirming that functional mitochondrial transfer is the primary driver. Our findings establish ADSC-EV-mediated mitochondrial transfer as a central metabolic reprogramming strategy that breaks the inflammatory lock in diabetic wounds and promotes healing.

Graphical Abstract