biostudies-literatureNiu LMedical Science and Technology Foundation of Guangdong ProvinceNational Key R&D Program of ChinaPearl River Talent Recruitment ProgramBasic and Applied Basic Research Foundation of Guangdong ProvinceNational Natural Science Foundation of Chinae15712https://www.ebi.ac.uk/biostudies/studies/S-EPMC12499428biostudies-literatureUnknown12(37)Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and impaired Treg cell differentiation. Mesenchymal stem cell-derived exosomes (MSC-exos) hold promise for treating immune-related diseases, while their clinical application is hindered by the limited production and non-specific organ distribution. In this study, a combined engineering strategy is developed for MSC-exo 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-exo), 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^high Agg-exo with enhanced immunomodulatory properties, which showes superior therapeutic effect for SLE. Taken together, a newly dual-engineering strategy is developed to produce high-yield, Foxp1^high Agg-exo, which solved the limitation of low-yield production and non-specific organ distribution of MSC-exos. This innovative strategy holds great potential for the development of exosome-based therapies in autoimmune diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany)Engineered Foxp1<sup>high</sup> Exosomes Ameliorates Systemic Lupus Erythematosus.PMC12499428A2024558824010652019JC01Y1822019ZT08Y485823710052023A15151111242021YFA1100600Ou QLi ZShi SChen ZLei FTeng WMao XNiu LChen HRen QfalseEngineered Foxp1<sup>high</sup> Exosomes Ameliorates Systemic Lupus Erythematosus.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and impaired Treg cell differentiation. Mesenchymal stem cell-derived exosomes (MSC-exos) hold promise for treating immune-related diseases, while their clinical application is hindered by the limited production and non-specific organ distribution. In this study, a combined engineering strategy is developed for MSC-exo 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-exo), 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^high Agg-exo with enhanced immunomodulatory properties, which showes superior therapeutic effect for SLE. Taken together, a newly dual-engineering strategy is developed to produce high-yield, Foxp1^high Agg-exo, which solved the limitation of low-yield production and non-specific organ distribution of MSC-exos. This innovative strategy holds great potential for the development of exosome-based therapies in autoimmune diseases.2025-01-01T00:00:00Z2025 Oct2026-06-04T04:50:07.215Z2026-05-05T03:12:44.079ZS-EPMC124994284060571910.1002/advs.202415712