{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:39:26Z","timestamp":1793691566936,"version":"4.5.1"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2507100"],"award-info":[{"award-number":["2023YFC2507100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The limited donor lung pool for lung transplantation (LTx) is largely due to concerns over ischaemia\u2013reperfusion injury (IRI), a major cause of primary graft dysfunction (PGD). NLRP3 inflammasome activation is known to play a pivotal role in the onset of IRI. While human umbilical cord mesenchymal stromal cell\u2010derived extracellular vesicles (hucMSC\u2010EVs) have shown potential in reducing acute lung injury, their effects on NLRP3 activation in the context of LTx remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, engineered hucMSC\u2010EVs were delivered via nebulisation to mitigate IRI in rat LTx models. We utilised both a rat orthotopic LTx model and a cell cold preservation reperfusion model to evaluate the therapeutic efficacy of hucMSC\u2010EVs. Bulk\u2010RNA sequencing, single\u2010cell sequencing analysis, immunofluorescence and Western blot techniques were employed to assess NLRP3 inflammasome activation and inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nebulised hucMSC\u2010EVs were efficiently internalised by alveolar macrophages (AMs), significantly reducing lung injury and improving oxygenation in the LTx models. Mechanistically, the engineered hucMSC\u2010EVs, which enhance the expression of miR\u2010146a, can more effectively suppress the activation of the NLRP3 inflammasome by targeting the IRAK1\/TRAF6\/NF\u2010\u03baB pathway, resulting in decreased levels of IL\u20101\u03b2, IL\u201018 and other inflammatory cytokines. These findings highlight the potential of miR\u2010146a\u2010modified EVs in modulating innate immune responses to alleviate IRI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results demonstrate that nebulised delivery of engineered hucMSC\u2010EVs effectively mitigates IRI in LTx by inhibiting NLRP3 inflammasome activation. This innovative approach presents a promising strategy for enhancing donor lung preservation and improving post\u2010transplant outcomes in LTx.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:bold>Nebulized Delivery of miR\u2010146a Engineered hucMSC\u2010EVs Mitigates Ischemia\u2010Reperfusion Injury (IRI) in Lung Transplantation<\/jats:bold>. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell\u2010derived extracellular vesicles (hucMSC\u2010EVs) modified with miR\u2010146a 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.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>Mechanistic Insights: Inhibition of NLRP3 Inflammasome Activation<\/jats:bold>. Engineered hucMSC\u2010EVs efficiently targeted alveolar macrophages and suppressed NLRP3 inflammasome activation through the IRAK1\/TRAF6\/NF\u2010\u03baB pathway. This modulation of innate immune responses played a crucial role in reducing IRI\u2010induced lung injury and inflammation, offering a promising strategy to manage primary graft dysfunction in lung transplantation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>Superior Efficacy of miR\u2010146a\u2010Modified EVs in Reducing Inflammatory Cytokines<\/jats:bold>. The miR\u2010146a modification enhanced the anti\u2010inflammatory properties of hucMSC\u2010EVs, leading to a more significant reduction in pro\u2010inflammatory cytokines (IL\u20101\u03b2, IL\u201018, and TNF\u2010\u03b1) compared to unmodified EVs. This targeted intervention presents a potential therapeutic avenue for improving lung transplant outcomes and mitigating IRI.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>Innovative Therapeutic Approach: Non\u2010Invasive Nebulization for Direct Lung Delivery<\/jats:bold>. The use of nebulized EVs for direct delivery to donor lungs represents a non\u2010invasive and efficient method for lung\u2010targeted therapy. This strategy could expand the applicability of MSC\u2010EV\u2010based treatments for improving lung transplantation outcomes, particularly in enhancing donor lung preservation during the procurement process.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70298","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T07:28:35Z","timestamp":1744097315000},"source":"Crossref","is-referenced-by-count":16,"title":["MiR\u2010146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia\u2013reperfusion injury in lung transplantation"],"prefix":"10.1002","volume":"15","author":[{"given":"Xiucheng","family":"Yang","sequence":"first","affiliation":[{"name":"Lung Transplantation Center Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang 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