Targeted delivery of dimethyl fumarate via CD40-directed PLGA nanoparticles to fibroblast-like synoviocytes suppresses inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, in which fibroblast-like synoviocytes (FLSs) play a central role by producing pro-inflammatory cytokines and matrix-degrading enzymes. Dimethyl fumarate (DMF) exhibits anti-inflammatory and antioxidant properties, partly through modulation of oxidative stress-related pathways. In this study, anti-CD40 antibody-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with DMF were designed to enable targeted delivery to CD40-expressing FLSs isolated from the synovial fluid of patients with RA. Expression of CD40 and the FLS marker CD90 was confirmed prior to treatment. Following exposure to targeted nanoparticles, gene expression levels of inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), matrix metalloproteinase-3 (MMP-3), heme oxygenase-1 (HO-1), and galectin-1 were evaluated using quantitative real-time PCR. Targeted delivery of DMF was associated with a significant upregulation of HO-1 and galectin-1 and a reduction in IL-1β and MMP-3 expression compared with controls (P < 0.05). These findings suggest that CD40-directed PLGA nanoparticles may enhance the cellular specificity of DMF delivery to FLSs and modulate inflammatory and oxidative stress-related gene expression in RA, although further studies are required to clarify underlying mechanisms and validate these effects at the protein level.