Systemic regulation of rheumatoid arthritis by mesenchymal stem cells: from immune homeostasis to microbiota modulation.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and progressive joint destruction. Although conventional therapies effectively alleviate clinical symptoms, they are largely incapable of reversing irreversible joint damage and the underlying immune dysregulation. Mesenchymal stem cells (MSCs), with their dual capabilities in immunomodulation and tissue repair, have emerged as a promising new therapeutic strategy. This review delineates how MSCs and their derived extracellular vesicles exert multifaceted anti-inflammatory and immunosuppressive effects in RA. Locally, these mechanisms include modulating the Treg/Th17 cell balance, inhibiting the proliferation and invasion of fibroblast-like synoviocytes, and regulating the RANKL/OPG system to suppress osteoclast activity, while orchestrating the repair and regeneration of damaged joints primarily through the secretion of trophic factors and paracrine regulation of local bone metabolism. Importantly, beyond these local effects, this review highlights the novel 'gut-MSC-immune' axis, elucidating the potential pathway through which MSCs might systemically modulate immune homeostasis by influencing gut microbiota composition and mucosal barrier integrity. Although preliminary clinical trials have demonstrated a favorable safety profile and potential therapeutic feasibility of MSC-based interventions, its therapeutic outcomes are significantly influenced by patient heterogeneity and the hostile inflammatory microenvironment. To address these clinical bottlenecks and overcome interpatient therapeutic heterogeneity, we discuss the synergistic potential of microbiota-targeted interventions combined with MSC therapy. Finally, key priorities for future research are proposed, including standardizing MSC preparation protocols, optimizing administration regimens, and validating long-term efficacy and safety via large-scale multicenter clinical trials-efforts that will ultimately accelerate the clinical translation and clinical application of precision MSC-based therapy for RA.