Extracellular vesicles in Sjögren’s disease (SjD): pathogenic mechanisms, diagnostic biomarkers, and therapeutic opportunities

Abstract Nanoscale extracellular vesicles (EVs), including exosomes, have become important players in the etiology and potential management of Sjögren disease (SjD). By transporting bioactive substances—including proteins, microRNAs (miRNAs), and autoantigens—between immune and epithelial cells, these vesicles promote intercellular communication, exacerbating glandular dysfunction and systemic autoimmunity. Remarkably, EVs extracted from SjD patients’ plasma and saliva contain unique molecular signatures, including specific proteomic profiles and miRNAs such as let-7b-5p and miR-142-3p. These EV-derived biomarkers offer promising non-invasive diagnostic and prognostic tools for early disease detection and stratification. On the other hand, the therapeutic potential of stem cell-derived EVs, particularly from mesenchymal stem cells (MSCs), presents a novel regenerative strategy. By modulating key immune responses—particularly by shifting macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype (thereby reducing M1-derived cytokines like TNF-α and IL-6), suppressing pathogenic B and T follicular helper cells via pathways including AKT/GSK-3β/Slug, RORC/IL-17 A, and NF-κB, and restoring the Th17/Treg balance—these MSC-EVs reduce inflammation, restore salivary and tear secretion, and promote tissue repair. Despite these encouraging preclinical developments, challenges regarding standardization, isolation methods, and clinical translation remain. To fully realize their potential in transforming the management of Sjögren disease, future research must focus on optimizing EV-based applications for targeted therapy and validating their efficacy in human clinical trials.