Engineered Foxp1 high Exosomes Ameliorates Systemic Lupus Erythematosus

Abstract 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.