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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年12月24日

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  • Barathan Muttiah,
  • Asrul Abdul Wahab

摘要

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.