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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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ph18091379","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T11:19:31Z","timestamp":1758021571000},"page":"1379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical Evaluation of Nanoemulsion and Polymeric Nanocapsule Delivery Systems of 4-(Phenylselanyl)-2H-Chromen-2-One for Rheumatoid Arthritis and Comorbidities"],"prefix":"10.3390","volume":"18","author":[{"given":"Caren Aline Ramson","family":"da Fonseca","sequence":"first","affiliation":[{"name":"Graduate Program in Biochemistry and Bioprospecting, Preclinical and Translational Research Group on Pain and Chronic Diseases, Federal University of Pelotas, Pelotas CEP 96010-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5185-6915","authenticated-orcid":false,"given":"Vinicius Costa","family":"Prado","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Technology, Graduate Program in Pharmaceutical Sciences, Health Sciences Center, Federal University of Santa Maria, Santa Maria CEP 97105-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6230-4577","authenticated-orcid":false,"given":"Let\u00edcia","family":"Cruz","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Technology, Graduate Program in Pharmaceutical Sciences, Health Sciences Center, Federal University of Santa Maria, Santa Maria CEP 97105-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa Macedo Esteves","family":"da Rocha","sequence":"additional","affiliation":[{"name":"Graduate Program in Biochemistry and Bioprospecting, Preclinical and Translational Research Group on Pain and Chronic Diseases, Federal University of Pelotas, Pelotas CEP 96010-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Paula Bonato","family":"Wille","sequence":"additional","affiliation":[{"name":"Graduate Program in Biochemistry and Bioprospecting, Preclinical and Translational Research Group on Pain and Chronic Diseases, Federal University of Pelotas, Pelotas CEP 96010-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang\u00e9lica Schiavom dos","family":"Reis","sequence":"additional","affiliation":[{"name":"Graduate Program in Biochemistry and Bioprospecting, Preclinical and Translational Research Group on Pain and Chronic Diseases, Federal University of Pelotas, Pelotas CEP 96010-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Carlo","family":"Kazmierczak","sequence":"additional","affiliation":[{"name":"Graduate Program in Chemistry, Chemistry Department, Federal University of Santa Maria, Santa Maria CEP 97105-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4723-1925","authenticated-orcid":false,"given":"Ricardo Frederico","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Graduate Program in Chemistry, Chemistry Department, Federal University of Santa Maria, Santa Maria CEP 97105-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-9962","authenticated-orcid":false,"given":"Ethel Antunes","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Graduate Program in Biochemistry and Bioprospecting, Preclinical and Translational Research Group on Pain and Chronic Diseases, Federal University of Pelotas, Pelotas CEP 96010-900, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Radu, A.F., and Bungau, S.G. 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