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Mesenchymal stem cell\u2010derived exosomes (MSC\u2010exos) hold promise for treating immune\u2010related diseases, while their clinical application is hindered by the limited production and non\u2010specific organ distribution. In this study, a combined engineering strategy is developed for MSC\u2010exo via aggregation culture and genetic editing, achieving a substantial increase in both exosome yield and therapeutic specificity in SLE. First, MSCs produce a high yield of engineered exosomes through an aggregation culture engineering strategy (Agg\u2010exo), demonstrating immune organ targeting and promoting Tregs via the Foxp1\/STAT5\/Foxp3 axis. Then, MSCs are engineered by overexpressing Foxp1 in order to acquire Foxp1\n                    <jats:sup>high<\/jats:sup>\n                    Agg\u2010exo with enhanced immunomodulatory properties, which showes superior therapeutic effect for SLE. Taken together, a newly dual\u2010engineering strategy is developed to produce high\u2010yield, Foxp1\n                    <jats:sup>high<\/jats:sup>\n                    Agg\u2010exo, which solved the limitation of low\u2010yield production and non\u2010specific organ distribution of MSC\u2010exos. This innovative strategy holds great potential for the development of exosome\u2010based therapies in autoimmune diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202415712","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T04:51:27Z","timestamp":1751518287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Engineered Foxp1\n                    <sup>high<\/sup>\n                    Exosomes Ameliorates Systemic Lupus Erythematosus"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3542-0120","authenticated-orcid":false,"given":"Luhan","family":"Niu","sequence":"first","affiliation":[{"name":"South China Center of Craniofacial Stem Cell Research Hospital of Stomatology Sun Yat\u2010sen University Guangdong Provincial Key Laboratory of Stomatology Guangzhou 510080 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