IFN-γ-primed MSC extracellular vesicles attenuate rheumatoid arthritis via PD-L1-driven T-cell suppression and bone preservation.

Rheumatoid arthritis (RA) is a progressive autoimmune disorder characterized by aberrant T-cell activation with clinical outcomes often hindered by adverse effects and inadequate remission. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) hold promise for the treatment of autoimmune disorders, the mechanisms by which cytokine priming enhances their efficacy remain poorly characterized. In this study, we investigated the immunomodulatory effects of EVs derived from interferon-gamma (IFN-γ)-primed MSCs (IFN-γ-EVs) in a collagen-induced arthritis (CIA) murine model. These results demonstrate that IFN-γ-EVs administration markedly attenuated joint inflammation, bone erosion, and proinflammatory cytokine levels in CIA mice, surpassing the performance of native MSC-EVs and achieving therapeutic parity with methotrexate. IFN-γ-EVs suppress pathogenic T-cell proliferation and activation while promoting the secretion of anti-inflammatory cytokines. Mechanistically, IFN-γ priming upregulates programmed death-ligand 1 (PD-L1) on the EVs; the subsequent genetic ablation of PD-L1 completely abolished these therapeutic benefits, identifying PD-L1 as the pivotal mediator. These findings suggest that IFN-γ priming amplifies the immunoregulatory capacity of MSC-EVs through a PD-L1-dependent pathway, presenting a safe, cell-free therapeutic strategy for RA intervention.