Apoptotic extracellular vesicles restore homeostasis of the articular microenvironment for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a severe autoimmune disease with symptoms including synovial inflammation, cartilage erosion, and bone loss in RA lesions, which eventually lead to joint deformity and function loss. Most current treatments fail to achieve satisfying therapeutic outcomes with some adverse effects. Extracellular vesicles derived from apoptotic cells (apoEVs) have emerged as important mediators in intercellular communication regulating diverse physiological and pathological processes. In this study, we investigated the therapeutic efficacy of macrophage-derived and osteoclast-derived apoEVs (M phi-apoEVs and OC-apoEVs) on RA. The in vitro results showed that both M phi-apoEVs and OC-apoEVs induced macrophage repolarization toward the antiinflammatory M2 phenotype, promoted chondrocyte functions and chondrogenesis, and inhibited osteoclast formation and maturation. In addition, OC-apoEVs promoted osteogenic differentiation. The in vivo study on the CIA mouse model further demonstrated that apoEVs could couple various functions and exert synergistic effects on the joint with RA, as evidenced by the regression of synovial inflammation, the reversal of cartilage damage and bone erosion, and the preservation of joint structure. These findings demonstrated that M phi-apoEVs and OCapoEVs contributed to restoring the homeostasis of the overall microenvironment in the RA joint and highlighted their potential application as a promising alternative to treat RA.