Bioactive Oil Blend Nanoemulsion Attenuates Depression-like Behavior Through Modulation of Neuroimmune-Related Inflammatory Pathways in Experimental Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease frequently accompanied by depression, with persistent inflammation, oxidative stress, and neuroimmune dysfunction contributing to disease progression. This study evaluated the therapeutic efficacy of a Gum Arabic-stabilized bioactive oil blend nanoemulsion and investigated its underlying mechanisms using molecular docking and network pharmacology. Methods: A lyophilized nanoemulsion prepared from grape seed oil, wheat germ oil, and avocado peel oil was characterized for physicochemical properties and phytochemical composition. Female rats with Freund’s complete adjuvant-induced rheumatoid arthritis received the nanoemulsion at two doses. Paw inflammation, behavioral performance, inflammatory cytokines, oxidative stress biomarkers, acetylcholinesterase concentration, lipid profile, and liver and kidney function were evaluated. Molecular docking and network pharmacology analyses were performed to identify potential molecular targets and signaling pathways. Results: The nanoemulsion exhibited favorable physicochemical characteristics and was rich in phenolic compounds, flavonoids, phytosterols, tocopherols, and unsaturated fatty acids. Treatment significantly reduced paw inflammation, TNF-α, IL-6, malondialdehyde, and acetylcholinesterase while enhancing catalase activity, improving metabolic parameters, and alleviating depression-like behavior. Molecular docking demonstrated favorable binding of the major phytochemicals to TNF-α, IL-6, and acetylcholinesterase. Network pharmacology identified key therapeutic targets, including TNF, AKT1, PTGS2, IL6, STAT3, ESR1, and NR3C1, and revealed enrichment of inflammatory, oxidative stress, and neuroimmune signaling pathways. Conclusions: The Gum Arabic-stabilized bioactive oil blend nanoemulsion ameliorated rheumatoid arthritis-associated depression-like behavior through a multi-component–multi-target–multi-pathway mechanism involving coordinated regulation of inflammatory, oxidative stress, cholinergic, and neuroimmune pathways. These findings support its potential as a complementary nutraceutical strategy for rheumatoid arthritis and its associated neurobehavioral complications.