Engineered Foxp1high Exosomes Ameliorates Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) features immune dysregulation and Treg cell dysfunction. While biologics reduce corticosteroid dependence, current treatments cause significant oral complications. Although mesenchymal stem cell-derived exosomes (MSC-exos) show therapeutic potential, their clinical use is limited by low yield and poor targeting. This study develops engineered MSC-exos for precise SLE treatment. This study establishes an MSC aggregation culture system to isolate engineered aggregated exosome(Agg-exo) and evaluates their SLE therapeutic effects. Using in vivo tracking and immune profiling, we characterize Agg-exo's biodistribution and immunomodulation. Proteomic analysis identifies key functional proteins, which are mechanistically validated. Finally, we develop a dual-engineering strategy combining MSC genetic modification with aggregation culture to enhance exosome therapy for SLE. We established an MSC aggregation culture system yielding high-protein Agg-exo. In vivo tracking showed Agg-exo were selectively taken up by immune organs and CD4+ T cells. Foxp1-enriched Agg-exo promoted Treg differentiation via Foxp1/STAT5/Foxp3 signaling. Dual engineering (gene-editing + aggregation) generated Foxp1high Agg-exo that effectively mitigated lupus symptoms. We developed a newly dual-engineering strategy to produce high-yield, Foxp1high Agg-exo, which solved the limitation of low-yield production and non-specific organ distribution of MSC-exo. This innovative strategy holds great potential for the development of exosome-based therapies in autoimmune diseases.