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Res."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Ischemic stroke is a leading cause of disability worldwide, with current therapies mainly focused on clot fibrinolysis rather than neuroprotection. Nestorone\n                    <jats:sup>\u00ae<\/jats:sup>\n                    (NES), a highly selective progesterone receptor agonist, has shown neuroprotective potential in experimental stroke. However, NES exhibits poor water solubility and high hepatic first-pass metabolism, limiting its oral bioavailability, which motivated us to develop new lipid-based NES formulations for nose-to-brain delivery. With that rationale, a nanoemulsion (NE) and a self-microemulsifying drug delivery system (SMEDDS) were herein evaluated for NES intranasal delivery post-stroke in mice. NES-loaded SMEDDS and NE aqueous dispersions showed highly homogeneous droplet sizes of approximately 20 and 90 nm. NES permeation across the MucilAir\u2122 model was significantly higher with the NE, which also demonstrated excellent in vitro safety. The SMEDDS decreased resazurin reduction, induced a small increase in LDH release, and caused a transient TEER decrease (&lt;\u2009100 \u2126\u00b7cm\u00b2) that recovered within 4 days. In mice, both intranasal formulations produced higher and faster plasma and brain NES Cmax values (tmax 5 min) compared with subcutaneous administration. Intranasal SMEDDS achieved the highest brain Cmax and significantly greater brain\/plasma NES concentration ratios. A single low NES-SMEDDS intranasal dose administered 1 h after stroke induction reduced infarct volume by 27% compared with saline (7.55\u2009\u00b1\u20090.99% vs. 10.33\u2009\u00b1\u20090.43%) and improved locomotor asymmetries. This effect was correlated with a less reactive astrocyte and microglia morphology at 48 h after ischemia. These results highlight intranasal NES-SMEDDS as a promising neuroprotective strategy warranting further preclinical and clinical investigation.\n                  <\/jats:p>","DOI":"10.1007\/s13346-026-02150-5","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T17:37:06Z","timestamp":1779557826000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low dose intranasal nestorone self-emulsifying drug delivery system promotes neuroprotection in experimental stroke through modulation of glial cells"],"prefix":"10.1007","author":[{"given":"Sara","family":"Meirinho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana Alves","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Diniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberto","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narender","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regine","family":"Sitruk-Ware","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaohong","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Navarro-Oviedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas M","family":"Pradillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Lizasoain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gra\u00e7a","family":"Baltazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana O.","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"2150_CR1","doi-asserted-by":"publisher","first-page":"E137","DOI":"10.1212\/WNL.0000000000207387","volume":"101","author":"J Fan","year":"2023","unstructured":"Fan J, Li X, Yu X, Liu Z, Jiang Y, Fang Y, et al. 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Santos and Gilberto Alves are inventors on a patent application related with the nanoemulsion described in this manuscript (WO2022259205A1), title \u201cSelf-emulsifying composition, production methods and uses thereof\u201d, filed June 9th, assigned to University of Beira interior, of which the related European patent EP4351515A1 and the United States patent US20240277615A1 are pending. Regine Sitruk-Ware is an inventor on the use of Nestorone for neuroprotection, United States Patent 9,446,051 B2, to Sitruk-Ware, Schumacher, Brinton, El-Etr, Ghoumari and Guennoun, titled, \u201cNeuroprotection and Myelin Repair Using Nestorone,\u201d filed December 21, 2012. Issued September 20, 2016; and United States patent 10,052,335 to Sitruk-Ware, Schumacher, Brinton, El-Etr, Ghoumari and Guennoun, entitled, \u201cNeuroprotection and Myelin Repair Using Nestorone,\u201d filed October 19, 2010. Issued August 21, 2018. Authors Sara Meirinho, Catarina Diniz, Susana Alves Ferreira, Shimin Zhang, Narender Kumar, Gaohong Di, Manuel Navarro-Oviedo, Jes\u00fas M Pradillo, Ignacio Lizasoain and Gra\u00e7a Baltazar declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"All institutional and national guidelines for the care and use of laboratory animals were followed. The experimental protocols were reviewed and approved, either by the competent national authority [Portuguese General Directorate for Food and Veterinary (DGAV \u2013 Dire\u00e7\u00e3o Geral de Alimenta\u00e7\u00e3o e Veterin\u00e1ria)], in agreement with the regulations of the European Directive 2010\/63\/EU and Portuguese law (Decreto-Lei n\u00ba 113\/2013): reference 0421\/000\/000\/2023 002871); or by the Animal Welfare Committee of Universidad Complutense de Madrid, Centro Nacional de Investigaciones Cardiovasculares and Consejer\u00eda de Medio Ambiente y Ordenaci\u00f3n del Territorio de la Comunidad de Madrid (Real Decreto [RD] 53\/2013; PROEX 016\/18 and 219.3\/24) following European directives 86\/609\/ Comunidad Econ\u00f3mica Europea (CEE) and 2010\/63\/ European Union (EU) and reported in accordance with Animal Research: Reporting of In Vivo Experiment guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}