Cellular stress, cell death, and extracellular vesicles: redefining the therapeutic landscape of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by dysregulated immune responses, persistent synovial inflammation, and progressive joint destruction. Neutrophil extracellular trap-mediated cell death (NETosis) and autophagy are interrelated processes that amplify inflammation and perpetuate autoimmunity in a feed-forward manner, accelerating synovial damage. Mesenchymal stem cells (MSCs) have attracted interest due to their strong immunomodulatory and regenerative potential; however, the safety concerns, engraftment, and long-term persistence led to focusing on mesenchymal stem cells' extracellular vesicles (MSC-EVs) as a cell-free alternative. MSC-EVs recapitulate many of the immunoregulatory benefits of MSCs, including suppression of pathogenic T-cell responses, restoration of Th17/Treg balance, polarization of macrophages into an anti-inflammatory phenotype, inhibition of NK-cell overactivation, and modulation of synovial fibroblast invasiveness through miRNA cargo. Preclinical and early clinical studies demonstrate the ability of MSC-EVs to reduce synovial inflammation, pannus formation, bone erosion, and cytokine dysregulation in models of RA, with apparently improved safety, stability, and scalability compared with cell-based therapies. This review focuses on the mechanistic interplay of NETosis and autophagy in RA, the therapeutic potential of MSCs, and the burgeoning evidence supporting MSC-EVs as a next-generation therapeutic platform in the management of RA.