Autophagy activation within inflammatory microenvironment improved the therapeutic effect of MSC-Derived extracellular Vesicle in SLE.

Introduction: Developing strategies to improve the therapeutic efficacy of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in autoimmune diseases have garnered increased attention.

Objectives: To evaluate whether rapamycin-induced autophagy within the systemic lupus erythematosus (SLE) inflammatory microenvironment (Rapa-SLE) augments the therapeutic effects of MSC-derived EVs in SLE.

Methods: The therapeutic potential of the resulting EVs (Rapa-SLE-EV) was assessed in MRL/lpr mice. Rapa-SLE-EVs were compared with EVs derived from MSCs from MSCs cultured with EV-depleted fetal bovine serum (FBS-EV), EVs from MSCs cultured with rapamycin-treated FBS (Rapa-FBS-EV), and EVs exposed to SLE serum without rapamycin (SLE-EV). The autoimmune response, renal function, and pathological damage were assessed among the mouse groups. Additionally, mechanistic investigations into the role of the anti-inflammatory protein IDO1 within the EVs.

Results: Interaction with the SLE inflammatory microenvironment triggered autophagy in MSCs, which was further enhanced by rapamycin treatment. Rapa-SLE-EV administration significantly ameliorated the autoimmune response and renal damage in MRL/lpr mice, outperforming other MSC-EV groups. This treatment mitigated key manifestations of SLE, including reduced autoantibody levels, as well as splenomegaly, and lymphadenopathy. Furthermore, Rapa-SLE-EV demonstrated superior suppression of plasma inflammatory cytokines, preserved renal function, mitigated pathological damage, and reduced glomerular immune complex deposition. Mechanistically, Rapa-SLE-EV exhibits exceptional inhibitory effects on SLE-B cell function, benefited by the high expression of the anti-inflammatory protein IDO1, which was confirmed to enter SLE-B cells through EVs.

Conclusions: We developed a novel strategy to improve the therapeutic efficacy of MSC-EVs in SLE and confirmed that the immunomodulatory function of the MSC-EVs is enhanced through autophagic activation and interaction with the SLE serum microenvironment, a process likely benefited by the high expression of IDO1.