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is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood\u2013brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid\u2013polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 \u00b0C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.<\/jats:p>","DOI":"10.3390\/ijms26052146","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T02:48:37Z","timestamp":1740710917000},"page":"2146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8112-7550","authenticated-orcid":false,"given":"Brandon","family":"Aguiar","sequence":"first","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1615-7797","authenticated-orcid":false,"given":"Ana Rita","family":"Alfenim","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"given":"Cl\u00e1udia Sofia","family":"Machado","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8649-941X","authenticated-orcid":false,"given":"Joana","family":"Moreira","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-4577","authenticated-orcid":false,"given":"Miguel","family":"Pinto","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-2253","authenticated-orcid":false,"given":"Francisco J.","family":"Otero-Espinar","sequence":"additional","affiliation":[{"name":"Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, Insitute of Materials (iMATUS), University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain"},{"name":"Health Research Institute of Santiago (IDIS), 15706 Santiago de Compostela, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0102-0703","authenticated-orcid":false,"given":"Carlos","family":"Fernandes","sequence":"additional","affiliation":[{"name":"CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R.Campo Alegre s\/n, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/S1474-4422(14)70179-6","article-title":"Therapy of amyotrophic lateral sclerosis remains a challenge","volume":"13","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","article-title":"Amyotrophic lateral sclerosis","volume":"390","author":"Hardiman","year":"2017","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1007\/s40265-022-01769-1","article-title":"Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents","volume":"82","author":"Johnson","year":"2022","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.freeradbiomed.2005.11.003","article-title":"Iron chelation in the biological activity of curcumin","volume":"40","author":"Jiao","year":"2006","journal-title":"Free Radic. 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