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

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, we discovered strong correlations among the cell-free DNA (cfDNA) level and the inflammatory response in clinical synovial fluid samples and RA disease activity. We also demonstrated the important role of cfDNA in disease development in collagen-induced arthritis (CIA) murine model. Building on these findings, we developed a novel therapeutic based on anti-inflammatory (M2) macrophage-derived exosomes as chassis that we modified with both oligolysine and matrix metalloproteinase (MMP)-cleavable polyethylene glycol (PEG) on the membrane. After intravenous injection, PEG-enabled prolonged circulation and C-C motif chemokine ligand (CCL)-directed accumulation together resulted in enrichment at inflamed joints. Following subsequent MMP cleavage, the positively charged oligolysine was exposed for cfDNA scavenging, while exosomes induced M2 polarization. By using a classical CIA murine model and a newly established CIA canine model, we demonstrated that our rationally designed exosome therapeutic substantially suppressed inflammation in joints and provided strong chondroprotection and osteoprotection, revealing its potential for effective CIA amelioration. This article is protected by copyright. All rights reserved.