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Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease. Activated macrophages in arthritic joints play a prominent role in the initiation and persistence of RA. Despite great progress in the clinical treatment of RA, poor response and high discontinuation due to systemic toxicity remain unsolved issues, especially the well-known methotrexate (MTX). Therefore, active targeted delivery of therapeutic drugs to pathogenic cells in arthritic joints is essential to increase  in situ  activity and decrease systemic toxicity. Here, we developed an MTX-loaded macrophage-targeted nano-emulsion (NE) based on the overexpression of folate receptor (FR) on activated macrophages, the inherent high affinity of FR for folate (FA), as well as the property of MTX and phospholipids to form complexes (MTX@PC). Intravenous injection of DID-labelled MTX@PC-FA NEs into adjuvant-induced arthritis (AIA) mice,  in vivo  images and flow cytometry results revealed that the NEs were highly targeted to inflamed joints and macrophages, respectively. Therapeutic studies suggested that this strategy was conducive to achieve high efficacy and low toxicity of MTX in the treatment of RA. Our research highlights MTX@PC-FA NEs as a potential treatment option for RA targeting the FR-expressed activated macrophages.

Folate receptor-mediated targeted therapy for rheumatoid arthritis by methotrexate-phospholipid complex nano-emulsions