Synergistic Modulation of Macrophages by Methotrexate and RELA siRNA Folate-Liposome: A Precision Therapy to Prevent Joint Degradation in Collagen-Induced Arthritic Rats

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and joint destruction. Current treatments, such as Methotrexate (MTX), while effective, often have therapeutic limitations like high plasma C max and lack of sustained release. This study explores a synergistic approach to RA therapy using folate-liposomal co-delivery of MTX and RELA siRNA, aimed at RAW264.7 macrophage repolarization through inhibition of the NF-κB pathway. Extensive invitro characterizations demonstrate the stability and biocompatibility of this combinatorial therapy in folate-liposomes. In collagen-induced arthritis (CIA) rat model, we observed a reduction in synovial inflammation and improved mobility following treatment. The combined MTX and RELA siRNA approach indirectly inhibits inflammatory cytokines and other biochemical parameters such as Rheumatoid factor (RF) and C-reactive protein (CRP). The targeted macrophage delivery yields a marked therapeutic effect in RAW264.7 murine macrophages, potentially modulating the M1 to M2 macrophage polarization. Overall, this research presents a promising avenue for innovative therapies in RA management by inhibiting the inflammatory cascade and preventing joint damage.