Exosome-mediated immunomodulation of osteoarthritic synovitis: macrophage fibroblast crosstalk, targeted delivery, and clinical translation

Osteoarthritis (OA) is a whole-joint disorder in which synovial inflammation plays an important role in pain, cartilage loss, fibrosis, and joint progression. Traditional systemic and intra-articular treatments offer relief, have a short duration of joint presence, lack complete cell targeting, and have side effects. Exosomes are membrane-enclosed extracellular vesicles that serve as vehicles to safeguard pharmacological cargo, mediate cellular uptake, and target the inflammatory tissues of the joints. This review discusses exosome-mediated targeted drug delivery to the synovial space for OA treatment, focusing on inflammatory mechanisms, carrier engineering, pharmacokinetics, therapeutic efficacy, safety, and clinical translation. Exosomes originating from mesenchymal stromal cells, chondrocytes, macrophages, and other cells can regulate synovial macrophages and fibroblast-like synoviocytes, inhibit the activation of cytokines and inflammasomes, inhibit the production of matrix-degrading enzymes, and protect the mitochondrial and autophagic functions of chondrocytes. Intra-articular persistence, small molecule loading, protein and regulatory nucleic acid loading, ligand display, and hydrogel-based retention may enhance potency. Most of this evidence is preclinical, and the reported benefits are limited by the lack of a uniform definition of vesicles, poorly standardized dosing, uncertain synovial specificity, limited pharmacokinetic data, and a lack of long-term safety evaluation. To develop a clinical product, scalable good manufacturing practices are needed, as well as assays for potency based on the mechanism of action, reproducible loading of the cargo, quantitative biodistribution, and controlled trials with patients with synovitis.