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Background <p>Lung ischemia–reperfusion injury (IRI) is a major contributor to primary graft dysfunction (PGD) after lung transplantation. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic agents in inflammatory diseases by ameliorating tissue damage and promoting repair. However, the anti-inflammatory efficacy of these approaches and the underlying mechanisms in lung ischemia–reperfusion injury remain incompletely understood.</p> Methods <p>The protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) against lung ischemia–reperfusion injury were evaluated using two delivery approaches, inhalation and intravenous injection. Both in vivo and in vitro models were employed to assess the biological activity of MSC-EVs and to elucidate the underlying molecular mechanisms. In addition, a rat orthotopic lung transplantation (OLT) model was established to further examine the translational relevance of MSC-EVs.</p> Results <p>MSC–EVs treatment significantly ameliorated lung IRI, with inhalation showing superior efficacy over intravenous delivery. Mechanistically, miR-22-3p within MSC-EVs targeted macrophage NLRP3, suppressing activation of the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. The protective efficacy was confirmed in a clinically relevant rat OLT model, underscoring their translational potential</p> Conclusions <p>Our findings indicate that inhaled MSC-derived extracellular vesicles attenuate lung ischemia–reperfusion injury by promoting macrophage polarization via the miR-22-3p/NLRP3/IL-1β pathway, supporting their potential as a cell-free therapeutic approach to mitigate primary graft dysfunction after lung transplantation.</p>

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Inhalation of mesenchymal stromal cell‐derived extracellular vesicles activates macrophage polarization through the miR-22-3p/NLRP3/IL-1β pathway, ameliorating lung ischemia - reperfusion injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月9日

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  • Tao Wang,
  • Guodong Wu,
  • Peigen Gao,
  • Fenghui Zhuang,
  • Zeyu Wang,
  • Ziheng Zhou,
  • Chongwu Li,
  • Junqi Wu,
  • Deping Zhao

摘要

Background

Lung ischemia–reperfusion injury (IRI) is a major contributor to primary graft dysfunction (PGD) after lung transplantation. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic agents in inflammatory diseases by ameliorating tissue damage and promoting repair. However, the anti-inflammatory efficacy of these approaches and the underlying mechanisms in lung ischemia–reperfusion injury remain incompletely understood.

Methods

The protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) against lung ischemia–reperfusion injury were evaluated using two delivery approaches, inhalation and intravenous injection. Both in vivo and in vitro models were employed to assess the biological activity of MSC-EVs and to elucidate the underlying molecular mechanisms. In addition, a rat orthotopic lung transplantation (OLT) model was established to further examine the translational relevance of MSC-EVs.

Results

MSC–EVs treatment significantly ameliorated lung IRI, with inhalation showing superior efficacy over intravenous delivery. Mechanistically, miR-22-3p within MSC-EVs targeted macrophage NLRP3, suppressing activation of the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. The protective efficacy was confirmed in a clinically relevant rat OLT model, underscoring their translational potential

Conclusions

Our findings indicate that inhaled MSC-derived extracellular vesicles attenuate lung ischemia–reperfusion injury by promoting macrophage polarization via the miR-22-3p/NLRP3/IL-1β pathway, supporting their potential as a cell-free therapeutic approach to mitigate primary graft dysfunction after lung transplantation.