A Targeted Exosome Therapeutic Confers Both CfDNA Scavenging and Macrophage Polarization for Ameliorating Rheumatoid Arthritis

Abstract Only a minority of rheumatoid arthritis (RA) patients achieve disease remission, so the exploration of additional pathogenic factors and the development of new therapeutics are needed. Here, strong correlations among the cell‐free DNA (cfDNA) level and the inflammatory response in clinical synovial fluid samples and RA disease activity are discovered. The important role of cfDNA in disease development in a collagen‐induced arthritis (CIA) murine model is also demonstrated. Building on these findings, a novel therapeutic based on anti‐inflammatory (M2) macrophage‐derived exosomes as chassis, that are modified with both oligolysine and matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) on the membrane, is developed. After intravenous injection, PEG‐enabled prolonged circulation and C─C motif chemokine ligand‐directed accumulation together result in enrichment at inflamed joints. Following subsequent MMP cleavage, the positively charged oligolysine is exposed for cfDNA scavenging, while exosomes induce M2 polarization. By using a classical CIA murine model and a newly established CIA canine model, it is demonstrated that the rationally designed exosome therapeutic substantially suppresses inflammation in joints and provides strong chondroprotection and osteoprotection, revealing its potential for effective CIA amelioration.