{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:08:01Z","timestamp":1785146881134,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology","award":["10.54499\/UIDB\/00709\/2020"],"award-info":[{"award-number":["10.54499\/UIDB\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["10.54499\/UIDP\/00709\/2020"],"award-info":[{"award-number":["10.54499\/UIDP\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["UID\/06397\/2025"],"award-info":[{"award-number":["UID\/06397\/2025"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["2021.03946.CEECIND"],"award-info":[{"award-number":["2021.03946.CEECIND"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>To reach the target tissue within the central nervous system (CNS), drugs, such as donepezil (DNPZ), must overcome naturally occurring barriers. Despite its substantial pharmacological relevance, the blood\u2013cerebrospinal fluid barrier (BCSFB) remains insufficiently studied. The BCSFB harbors a functional molecular clock that regulates, for instance, the expression of membrane transporters. Thus, there has been an increasing interest in exploring chronotherapeutic strategies to enhance cerebral drug delivery. Additionally, nanotechnology constitutes a well-established approach for improving tissue-specific drug bioavailability within the CNS through, for example, the employment of chitosan (CS)-based nanosystems. Given the considerable potential of both approaches for the treatment of neurological disorders, we propose establishing an integrated chronotherapy\u2013nanotechnology platform to optimize pharmacological regimens. In this context, this study aims to explore the influence of circadian rhythms in the transport of free and encapsulated DNPZ forms across an in vitro model of the BCSFB. We developed and characterized CS-based nanoparticles with promising properties for the enhanced delivery of DNPZ across brain barriers. We found that free and encapsulated drug forms of DNPZ display distinct patterns of circadian trafficking across BCSFB. In summary, our findings represent an important step toward the integration of chronotherapy and nanotechnology as a promising strategy to optimize therapeutic outcomes.<\/jats:p>","DOI":"10.3390\/ijms27156644","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chrono-Nanomedicine at the Barrier: Circadian Rhythms Influence the Delivery of Donepezil Across the BCSFB"],"prefix":"10.3390","volume":"27","author":[{"given":"Maria Rodrigues","family":"Cardoso","sequence":"first","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5911-6521","authenticated-orcid":false,"given":"Ana Catarina","family":"Duarte","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Mineiro","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5595-204X","authenticated-orcid":false,"given":"Miguel","family":"Ferreira","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9155-7581","authenticated-orcid":false,"given":"\u00c2ngela","family":"Sousa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-8998","authenticated-orcid":false,"given":"Eugenia","family":"Gallardo","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Pharmacology and Toxicology Laboiratory, UBIMedical, University of Beira Interior, 6200-000 Covilh\u00e3, Portugal"},{"name":"Problem Group Related to Substance Dependence, Beiras Academic Clinical Center (CACB), 6200-000 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-0682","authenticated-orcid":false,"given":"Hiroshi","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-0259","authenticated-orcid":false,"given":"Christian","family":"Schwerk","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, 69117 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6779-1084","authenticated-orcid":false,"given":"Horst","family":"Schroten","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, 69117 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6074-7825","authenticated-orcid":false,"given":"Cec\u00edlia","family":"Santos","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-4518","authenticated-orcid":false,"given":"Diana","family":"Costa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-9858","authenticated-orcid":false,"given":"Telma","family":"Quintela","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"UDI-IPG\u2014Unit for yhe Development of the Interior, Polytechnic University of Guarda, 6300-559 Guarda, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rostagno, A.A. (2022). Pathogenesis of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010107"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115522","DOI":"10.1016\/j.bcp.2023.115522","article-title":"Alzheimer\u2019s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs","volume":"211","author":"Monteiro","year":"2023","journal-title":"Biochem. 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