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

Background： Lung ischemia/reperfusion injury (LIRI) is a primary contributing factor to the occurrence of primary graft dysfunction. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) can ameliorate tissue damage and promote recovery in animal models of inflammatory diseases. However, the capacity of MSC-EVs to induce an anti-inflammatory effect in LIRI remains unclear. Methods: In this study, we used two administration methods, inhalation and intravenous injection, to investigate the role and activity of MSC-EVs in pulmonary ischemia‒reperfusion injury. Furthermore, through in vivo and in vitro experiments to explored the role and mechanism of MSC-EVs in LIRI. Results: we elucidated that MSC-EVs alleviate LIRI by promoting the polarization of macrophages from the M1 to M2 phenotype. Mechanistically, we revealed that miR-22-3pwithin MSC-EVs directly targets and inhibits the expression of NLRP3, consequently suppressing the NLRP3/caspase-1/IL-1β pathway and facilitating the transition of macrophages toward the M2 phenotype. Conclusions: Collectively, our data show that Inhalation of MSC-EVs activates macrophage polarization through the miR-22-3p/NLRP3/IL-1β pathway, ameliorating pulmonary IRI.