Oral ginger-derived extracellular vesicles ameliorate arthritis via anti-inflammatory actions of microRNA-149 and 6-gingerol

Ginger-derived extracellular vesicles (GDEVs) have emerged as a novel anti-inflammatory agent with advantages such as oral bioavailability, natural origin, and cost-effective large-scale production. This study evaluated the therapeutic potential of GDEVs in rheumatoid arthritis (RA), a chronic autoimmune disease characterized by synovial inflammation and joint destruction. We conducted both <i>in vitro</i> and <i>in vivo</i> experiments using synovial fibroblasts derived from RA patients and a collagen antibody-induced arthritis (CAIA) mouse model. <i>In vitro</i>, GDEVs significantly suppressed the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β and downstream mediators IL-6, Cox-2, and matrix metalloproteinase 3 (MMP3) and inhibited the proliferation and migration of RA synovial fibroblasts. <i>In vivo</i>, oral administration of GDEVs to CAIA mice reduced arthritis severity, attenuated synovitis, preserved cartilage integrity, and suppressed osteoclast activation. GDEVs were stable against gastric digestion and were efficiently taken up by intestinal cells, supporting their oral availability. Microarray and RNA sequencing identified miR-149 as a key regulatory molecule in GDEVs, associated with the suppression of inflammation-related signaling pathways, including Ras signaling and mitogen-activated protein kinase (MAPK) cascades. These findings highlight the potential of GDEVs as an anti-inflammatory therapy for RA. Given their stability and bioavailability, the oral administration of GDEVs could be a promising non-invasive treatment for future clinical applications.