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Extracellular cytokine\u2010induced Wnt\u2010based signaling provides an alternative option for COPD treatment. However, the hydrophobic nature of Wnt proteins limits their purification and use. This study devises a strategy to deliver the membrane\u2010bound wingless\u2010type MMTV integration site family, member 3A (Wnt3a) over a long distance by anchoring it to the surface of extracellular vesicles (EVs). The newly engineered Wnt3a<jats:sup>WG<\/jats:sup> EVs are generated by co\u2010expressing Wnt3a with two genes encoding the membrane protein, WLS, and an engineered glypican, GPC6<jats:sup>\u0394GPI<\/jats:sup>\u2010C1C2. The bioactivity of Wnt3a<jats:sup>WG<\/jats:sup> EVs is validated using a TOPFlash assay and a mesoderm differentiation model of human pluripotent stem cells. Wnt3a<jats:sup>WG<\/jats:sup> EVs activate Wnt signaling and promote cell growth following human alveolar epithelial cell injury. In an elastase\u2010induced emphysema model, impaired pulmonary function and enlarged airspace are greatly restored by the intravenous delivery of Wnt3a<jats:sup>WG<\/jats:sup> EVs. Single\u2010cell RNA sequencing\u2013based analyses further highlight that Wnt3a<jats:sup>WG<\/jats:sup> EV\u2010activated regenerative programs are responsible for its beneficial effects. These findings suggest that EV\u2010based Wnt3a delivery represents a novel therapeutic strategy for lung repair and regeneration after injury.<\/jats:p>","DOI":"10.1002\/advs.202206606","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T23:05:59Z","timestamp":1681859159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Wnt3a\u2010Loaded Extracellular Vesicles Promote Alveolar Epithelial Regeneration after Lung Injury"],"prefix":"10.1002","volume":"10","author":[{"given":"Lei","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei Anhui 230027 China"},{"name":"Blood and Cell Therapy Institute Anhui Provincial Key Laboratory of Blood Research and Applications University of Science and Technology of China  Hefei Anhui 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