Injectable Glycosaminoglycan Hydrogel with Immunosuppressive Exosomes for Macrophage Polarization and Cartilage Repair in a Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and dysfunction. Although existing treatments can alleviate symptoms, they lack a comprehensive and effective approach for treating RA. Exosomes have gained widespread attention as excellent drug delivery carriers with therapeutic potential. Tumor-derived exosomes, owing to their immunosuppressive properties, hold promise for immune regulation and may positively impact the treatment of RA. This study presents a delivery system using a cartilage matrix hyaluronic acid-chondroitin sulfate hydrogel (HC hydrogel) loaded with methotrexate-loaded osteosarcoma-derived exosomes (Exo@MTX). The injectable self-healing HC hydrogel, along with the exosomes, enables sustained release of MTX via local injection, reducing the frequency of administration and minimizing side effects. Furthermore, the system components work synergistically, not only providing immune regulation and anti-inflammatory effects by scavenging reactive oxygen species (ROS) and modulating macrophage M2 polarization but also protecting chondrocytes and promoting joint cartilage repair. Overall, this system integrates anti-inflammatory, immunoregulatory, and cartilage repair effects, demonstrating excellent therapeutic efficacy in a collagen-induced arthritis (CIA) rat model. It offers a potential therapeutic strategy leveraging tumor-derived exosome-mediated immunosuppressive effects, presenting a significant stride in RA treatment strategies.