Berberine-Loaded Folate-Targeted Glycol Chitosan Nanocarrier (BFGCN) Modulates the Lipid–Immune–Bone Axis in Rheumatoid Arthritis Rat Model

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation, oxidative stress, and progressive bone degradation. Current studies inadequately address the interrelated metabolic and inflammatory processes that sustain disease progression. This study introduces a berberine-loaded folate-targeted glycol chitosan nanocarrier (BFGCN) that enables multidimensional modulation of RA pathogenesis by reprogramming the lipid–immune–bone axis. BFGCN demonstrated superior hemocompatibility (<4%) and significantly enhanced pharmacokinetics (C 0 = 34.44 μg mL –1, K = 0.114 h –1, t 1 / 2 = 6.04 h, AUC = 296.91 μg h mL –1, and CL = 0.067 L h –1 ) compared to free berberine (C 0 = 20.53 μg mL –1, K = 0.14 h –1, t 1 / 2 = 4.94 h, AUC = 159.45 μg h mL –1, and CL= 0.125 L h –1 ). In adjuvant-induced arthritic (AIA) rats, BFGCN selectively localized in inflamed joints, reduced paw edema, recovered body weight, and decreased arthritic scores. micro-CT and histology revealed the maintenance of trabecular bone architecture through the normalization of the RANKL/OPG axis. BFGCN mechanistically downregulated pro-inflammatory cytokines (TNF-α, IL-6), restored anti-inflammatory cytokines (IL-10, TGF-β), and re-established redox equilibrium by augmenting GST, GSH, and SOD activities while decreasing LDH and NO levels. BFGCN significantly reduced the autotoxin–lysophosphatidic acid (ATX–LPA) signaling pathway, an essential lipid mediator axis linking inflammation to cardiovascular risk, supported by molecular docking that exhibited strong berberine–LPA 1 binding. These converging effects diminished inflammation across the body, suppressed osteoclast activation, and reinstated metabolic homeostasis. This study identifies BFGCN as a multifunctional nanophytotherapeutic that encompasses anti-inflammatory, antioxidant, osteoprotective, and cardioprotective actions, offering a comprehensive framework for the holistic management of RA.