MiR‐146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia–reperfusion injury in lung transplantation

Nebulized Delivery of miR-146a Engineered hucMSC-EVs Mitigates Ischemia-Reperfusion Injury (IRI) in Lung Transplantation. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) modified with miR-146a to alleviate IRI in rat lung transplantation models. The treatment significantly improved lung oxygenation and reduced inflammation, highlighting the efficacy of this novel approach in enhancing donor lung preservation. Mechanistic Insights: Inhibition of NLRP3 Inflammasome Activation. Engineered hucMSC-EVs efficiently targeted alveolar macrophages and suppressed NLRP3 inflammasome activation through the IRAK1/TRAF6/NF-κB pathway. This modulation of innate immune responses played a crucial role in reducing IRI-induced lung injury and inflammation, offering a promising strategy to manage primary graft dysfunction in lung transplantation. Superior Efficacy of miR-146a-Modified EVs in Reducing Inflammatory Cytokines. The miR-146a modification enhanced the anti-inflammatory properties of hucMSC-EVs, leading to a more significant reduction in pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α) compared to unmodified EVs. This targeted intervention presents a potential therapeutic avenue for improving lung transplant outcomes and mitigating IRI. Innovative Therapeutic Approach: Non-Invasive Nebulization for Direct Lung Delivery. The use of nebulized EVs for direct delivery to donor lungs represents a non-invasive and efficient method for lung-targeted therapy. This strategy could expand the applicability of MSC-EV-based treatments for improving lung transplantation outcomes, particularly in enhancing donor lung preservation during the procurement process.