Exosome-mediated crosstalk in rheumatoid arthritis: Pathogenic mediators to next-generation therapeutics.

Rheumatoid arthritis (RA) is a debilitating chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction. Despite advancements in pharmacology, many patients exhibit suboptimal responses to conventional therapies, necessitating the development of innovative therapeutic paradigms. Extracellular vesicles (EVs), specifically exosomes, have emerged as pivotal mediators in RA pathophysiology, acting as dual-purpose orchestrators of both disease progression and therapeutic modulation. These nanosized vesicles facilitate intricate intercellular communication by transporting bioactive cargo-including miRNAs and proteins-from diverse origins such as immune cells, mesenchymal stem cells (MSCs), and the microbiota. Pathologically, EVs derived from inflammatory niches can exacerbate systemic inflammation and accelerate joint degradation. Conversely, therapeutic EVs, particularly those harvested from MSCs or engineered immune cells, exert potent immunomodulatory effects by suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-6), promoting M2 macrophage polarization, stabilizing the Th17/Treg balance, and inhibiting the activation of fibroblast-like synoviocytes (FLSs). Furthermore, bioengineering strategies now enable the utilization of EVs as precision drug delivery systems, enhancing the targeted transport of therapeutics like methotrexate. This review provides a comprehensive analysis of EV biogenesis and characterization, while consolidating evidence on their multifaceted roles in RA, highlighting their transformative potential as next-generation, cell-free diagnostic biomarkers and targeted therapeutic platforms.