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

• Inhalation of MSC-EVs significantly ameliorates lung ischemia-reperfusion injury, showing superior efficacy over intravenous delivery. • miR-22-3p within MSC-EVs targets macrophage NLRP3, suppressing the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. • The protective effects were confirmed in a clinically relevant rat orthotopic lung transplantation model, highlighting translational potential. • MSC-EVs offer a promising cell-free therapeutic strategy for preventing primary graft dysfunction after lung transplantation.