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 Cmax 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-?B 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.