Exosome-mediated immune modulation in rheumatoid arthritis and its role in synovial inflammation and autoimmune...

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent articular inflammation, cartilage destruction and aberrant synovial angiogenesis. While current cytokine-centric therapies have revolutionized RA management, their limitations highlight the need for a deeper understanding of the integrated synovial microenvironment. This review explores the critical role of exosomes as central regulatory nodes orchestrating intercellular communication within the RA joint. Under conditions of hypoxia and metabolic stress, exosomes secreted by fibroblast-like synoviocytes (FLS) and immune cells are dynamically loaded with pathogenic cargo, including microRNAs and autoantigens. These vesicles actively modulate macrophage phenotypes, moving beyond the traditional binary framework to reflect a continuum of pro-inflammatory activation, reprogram T-cells to favour pathogenic Th17 expansion while impairing regulatory T-cells (Tregs), and amplify autoreactive B-cell activation for sustained autoantibody production. While exosomes sustain the hypoxia-inflammation-angiogenesis axis and promote invasive pannus formation independently of transient soluble cytokines, we critically delineate which of these mechanisms are validated in RA-specific models against broader immunobiology. We propose that targeting these exosome-mediated signalling cascades offers a promising strategy to overcome therapeutic resistance, signifying their potential as novel therapeutic interventions and high-fidelity diagnostic biomarkers. Further, the significant translational, delivery, and standardization challenges are also addressed.