Diosmetin‐Loaded Solid Lipid Nanoparticles Attenuate Induced Arthritis via Cytokines Modulation and Antioxidant Activity

ABSTRACT Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by systemic inflammation, joint destruction, and oxidative stress. Despite advances in treatments, RA remains incurable, with current therapies often linked to adverse effects. This study investigated the anti‐arthritic potential of diosmetin encapsulated within solid lipid nanoparticles (D‐SL‐NPs), designed to enhance its bioavailability and therapeutic efficacy. D‐SL‐NPs, prepared via a modified hot plate encapsulation method, achieved 92.5% entrapment efficiency, a particle size of 7 nm, and a zeta potential of −16 mV. Significant in vitro anti‐inflammatory effects are observed with the D‐SL‐NPs‐III, including membrane stabilization (81%), protein denaturation inhibition (92%), and enhanced in vivo activities of SOD (52 U/mg), CAT (53 U/mg), and GSH (6.4 µg/mg). Moreover, D‐SL‐NPs‐III modulated cytokine expression by suppressing TNF‐α (0.17), IL‐1β (0.18), MMP‐13 (0.25), COX‐1 (0.28), and COX‐2 (0.19), while upregulating IL‐10 (0.7) and IL‐4 (0.93). Histopathological analysis confirmed restored joint integrity, while pharmacokinetic studies revealed a prolonged half‐life (T½ = 24 h) and improved bioavailability. These findings suggest that D‐SL‐NPs offer a safe and effective therapeutic strategy for autoimmune arthritis. This is the first study to demonstrate their efficacy in an autoimmune model, highlighting translational potential and the need for further clinical investigation.