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BACKGROUND Methotrexate (MTX) commonly used in rheumatoid arthritis (RA) has severe adverse effects. Ortho-vanillin, an inhibitor of Toll-like receptors (TLR), can prevent inflammation. Glucan is a cereal fiber recognized by dectin-1 or β-glucan receptors of phagocytic macrophages. The purpose of the current project was to study the effect of co-administration of MTX and vanillin by targeted delivery to macrophages using β-glucan microspheres to reduce inflammation of RA. METHODS MTX and vanillin nanoparticles in bovine serum albumin (