{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T09:47:05Z","timestamp":1765532825011,"version":"3.48.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160678"],"award-info":[{"award-number":["82160678"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Young Elite Scientists Sponsorship Program","award":["GASTYESS202420"],"award-info":[{"award-number":["GASTYESS202420"]}]},{"name":"Future Science and Technology Elite Talent Program of Zunyi Medical University","award":["ZYSE-2022-02"],"award-info":[{"award-number":["ZYSE-2022-02"]}]},{"name":"Science and Technology Planning Project of Zunyi","award":["ZKHHZ (2022)412"],"award-info":[{"award-number":["ZKHHZ (2022)412"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Cerebral ischemia\/reperfusion injury (CIRI) is a major challenge in ischemic stroke treatment. Phloretin (PHL), despite its potent antioxidant and anti-inflammatory properties, has limited clinical application due to poor oral bioavailability. This study aimed to develop an orally administered phloretin-loaded nanoemulsion (NE-PHL) to enhance brain delivery and neuroprotective efficacy against CIRI. Methods: NE-PHL was optimized via an orthogonal experimental design combined with ultrasonication. The optimized formulation was characterized for physicochemical properties and evaluated for pharmacokinetics and brain bioavailability. Its therapeutic efficacy was assessed in middle cerebral artery occlusion (MCAO) rats by measuring infarct volume, neurological scores, oxidative stress markers, and inflammatory cytokines. RNA sequencing analysis was performed to elucidate the underlying mechanisms. Results: The optimized NE-PHL exhibited a small droplet size (96.26 \u00b1 0.86 nm), high encapsulation efficiency (84.58 \u00b1 3.03%), and good storage stability over a period of 120 days. Pharmacokinetic studies showed a 2.72-fold increase in AUC 0\u201312h for NE-PHL compared to free PHL. In MCAO rats, NE-PHL treatment significantly improved neurological function, reduced cerebral infarct volume, attenuated oxidative stress, and modulated inflammatory responses by suppressing pro-inflammatory cytokines and enhancing anti-inflammatory activity. RNA sequencing analysis further confirmed coordinated downregulation of key pathways related to oxidative stress and inflammation. Conclusions: NE-PHL represents a promising oral nanotherapeutic strategy for the effective management of CIRI, offering enhanced bioavailability and significant neuroprotection.<\/jats:p>","DOI":"10.3390\/pharmaceutics17121599","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T15:43:43Z","timestamp":1765467823000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Delivery of Phloretin by Mixed Emulsifier-Stabilized Nanoemulsion Alleviated Cerebral Ischemia\/Reperfusion Injury"],"prefix":"10.3390","volume":"17","author":[{"given":"Tingting","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changjing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenchai","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houbo","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronghui","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyao","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuandong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1016\/S0140-6736(24)00642-1","article-title":"Stroke","volume":"403","author":"Hilkens","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.neuroscience.2023.04.028","article-title":"Retinoic Acid Has Neuroprotective effects by Modulating Thioredoxin in Ischemic Brain Damage and Glutamate-exposed Neurons","volume":"521","year":"2023","journal-title":"Neuroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e144898","DOI":"10.1172\/JCI144898","article-title":"Exogenous inter-\u03b1 inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice","volume":"131","author":"McCullough","year":"2021","journal-title":"J. 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