Engineered Foxp1^high 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.