{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T03:30:56Z","timestamp":1787974256581,"version":"build-2784847793"},"reference-count":79,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Hesperidin (HSP) is a potent phytochemical antioxidant and anti-inflammatory agent that protects against otitis media. However, due to its low solubility and bioavailability, a suitable delivery method is needed to overcome these problems. A hydrogel is a promising nanocarrier for controlled drug delivery in response to external stimuli, such as pH variations. Methods: Graphene oxide (GO)-based nanocarriers that encapsulate hesperidin (HSP) were further coated with a polylactic-co-glycolic acid\/alginate (PLGA-Alg) hydrogel before being integrated into a green neem oil (N.O.) double emulsion to produce a synergistic effect and then characterized by different assays. Results: The nanocarriers exhibited a substantial particle size (168 \u00b1 0.32 nm), with high encapsulation (89.86 \u00b1 0.23%) and a zeta potential of 37 \u00b1 0.43 mV. In vitro release studies conducted over 96 h indicated a sustained HSP release of 82% at pH 5.4 and 65% at pH 7.4. The GO-HSP-loaded neem oil double emulsion formulation exhibits substantial antibacterial activity, as evidenced by inhibition zones of 39 \u00b1 0.02 mm against Staphylococcus epidermidis, and considerable antifungal activity against Candida albicans, with an inhibition zone of 43 \u00b1 0.13 mm, along with biofilm inhibition activity. The formulation demonstrated antioxidant activity (5.21 \u00b5g\/mL) and increased cell viability (90\u201395%) while maintaining low cytotoxicity in HSE-2 cells. A histopathological analysis confirmed that treatment with the nanocarriers reduced the levels of pro-inflammatory cytokines (IL-1\u03b2, TNF-\u03b1, TLR4, IL-6) and raised the levels of antioxidant markers (Nrf-2, SOD) in an in vivo rat model of otitis media. Conclusions: GO-based nanocarriers integrated into a neem oil double emulsion and coated with PLGA-Alg hydrogel deliver hesperidin with sustained release and enhanced antibacterial, antifungal, and antioxidant properties. This formulation may be used to treat otitis media and other oxidative stress diseases.<\/jats:p>","DOI":"10.3390\/ph18030381","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T09:38:46Z","timestamp":1741340326000},"page":"381","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Polylactic-Co-Glycolic Acid\/Alginate\/Neem Oil-Reduced Graphene Oxide as a pH-Sensitive Nanocarrier for Hesperidin Drug Delivery: Antimicrobial and Acute Otitis Media Assessments"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7871-3313","authenticated-orcid":false,"given":"Saeed Abdul Kareem Saeed","family":"Al-Zuhairy","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Kut University College, Kut 52001, Wasit, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sammar Fathy","family":"Elhabal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Fathi","family":"Mohamed Elrefai","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan"},{"name":"Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-3332","authenticated-orcid":false,"given":"Sandra","family":"Hababeh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakline","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Nahda University, Beni-Suef (NUB), Beni-Suef 62511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Fady","sequence":"additional","affiliation":[{"name":"Infection Control Unit, Zagazig University Hospitals, Zagazig 44519, Egypt"},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla A.","family":"Elzohairy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt"},{"name":"Air Force Specialized Hospital, Cairo 19448, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tassneim M.","family":"Ewedah","sequence":"additional","affiliation":[{"name":"Pharmaceutics and Pharmaceutical Technology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim S.","family":"Mousa","sequence":"additional","affiliation":[{"name":"Pharmaceutics Department, Faculty of Pharmacy, Sinai University, Al-Arish 45511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4930-792X","authenticated-orcid":false,"given":"Ahmed Mohsen Elsaid","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16063","DOI":"10.1038\/nrdp.2016.63","article-title":"Otitis Media","volume":"2","author":"Schilder","year":"2016","journal-title":"Nat. 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