Platelet-derived exosomes in situ reprogramming macrophages for rheumatoid arthritis treatment.

M1 macrophages secrete various pro-inflammatory cytokines and play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Therefore, strategies aimed at eliminating synovial M1 macrophages or reprogramming them toward an anti-inflammatory M2 phenotype represent critical approaches for RA treatment. In this study, we propose a novel therapeutic strategy using platelet-derived exosomes (PLT-Exos) to induce the polarization of M1 macrophages into the anti-inflammatory M2 phenotype. Our results demonstrate that PLT-Exos are enriched with immunoregulatory proteins associated with M2 macrophage polarization and can effectively stimulate the conversion of M1 to M2 macrophages. Through phagocytosis assays and in vivo imaging, we confirmed that PLT-Exos are efficiently taken up and specifically accumulate in the joints of collagen-induced arthritis (CIA) mice. Treatment with PLT-Exos significantly reduced joint swelling, arthritis scores and synovial inflammation, while alleviating bone erosion and cartilage damage, leading to marked improvement in motor function in CIA mice. Notably, the therapeutic efficacy of PLT-Exos in RA was comparable to that of the clinical drug methotrexate (MTX), with excellent biocompatibility and no observed cytotoxicity. Overall, the use of PLT-Exos to induce M1-to-M2 macrophage polarization represents a promising therapeutic approach for RA and offers substantial potential for the development of anti-inflammatory treatments for various inflammatory diseases.