Preclinical Evaluation of Nanoemulsion and Polymeric Nanocapsule Delivery Systems of 4-(Phenylselanyl)-2H-Chromen-2-One for Rheumatoid Arthritis and Comorbidities.

Background/Objectives: Recognizing the current limitations in rheumatoid arthritis (RA) treatments, especially in managing pain and inflammation, there is an urgent need to develop and explore new therapeutic strategies. In this study, we devised two innovative approaches using nanotechnology for treating RA. We evaluated the effectiveness of compound 4-(phenylselanyl)-2H-chromen-2-one (4-PSCO) in three forms: free, as well as in nanoemulsified (4-PSCO NE) and nanoencapsulated (4-PSCO NC) formulations. Methods: Arthritis was induced in mice by intraplantar injection of Freund's complete adjuvant (CFA; 0.1 mL). The 4-PSCO free, 4-PSCO NE, and 4-PSCO NC (1 mg/kg, orally) treatments were administered daily for 15 days. We assessed disease signs, symptoms, mechanical and thermal sensitivities, neurobehavioral deficits, and activities of myeloperoxidase (MPO), Na⁺, K⁺-ATPase, and acetylcholinesterase (AChE), as well as oxidative stress markers. Results: Our study demonstrates, for the first time, that both 4-PSCO NC and 4-PSCO NE inhibit the clinical signs of RA in mice, including inflammation. Moreover, both formulations alleviated pain and anxiety behaviors while restoring AChE activity and decreasing oxidative stress in the cerebral cortex. Notably, only the 4-PSCO NC treatment increased the time animals spent in the open arms of the elevated plus-maze. It lowered TBARS levels in the cerebral cortex, spinal cord, and paws, showcasing its advantages over the free 4-PSCO and 4-PSCO NE. Conclusions: These findings highlight the therapeutic potential of 4-PSCO, especially the polymeric nanocapsule, as a practical option for treating both the symptoms and underlying mechanisms of RA.