Berberine-Loaded Nanoparticles Combat Oxidative and Nitrosative Stress to Reprogram Macrophages in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory processes leading to significant disability. While the role of reactive oxygen species (ROS) in mitochondrial damage and macrophage dysfunction is well-established, the contribution of nitrosative stress remains largely unexplored. This study investigated the impact of nitrosative stress-induced membrane damage, loss of mitochondrial membrane potential (MMP), and the imbalance between M1/M2 macrophages in RA progression. Current strategies to repolarize M2 cells face challenges due to the persistence of ROS activity in the synovial joint. To address this, we developed a cutting-edge nano-therapy: Berberine-loaded folate-glycol chitosan nanoparticles (BFGCN), synthesized via nano-precipitation with a zero-order cross-linking technique. These spherical nanoparticles (~ 150 nm) were engineered to specifically target folate receptor-β (FR-β) on activated macrophages, confirmed through molecular docking studies. BFGCN demonstrated remarkable efficacy in reducing oxidative/nitrosative stress, restoring MMP, and promoting the repolarization of anti-inflammatory M2 macrophages. Our findings underscore the critical role of redox imbalances in RA pathogenesis, offering a promising therapeutic strategy for modulating macrophage reprogramming and mitigating disease progression.