{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T08:04:24Z","timestamp":1784880264407,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["252300423780"],"award-info":[{"award-number":["252300423780"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["252300423781"],"award-info":[{"award-number":["252300423781"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Henan Eye Hospital Basic Science Research Program","award":["25JCQN009"],"award-info":[{"award-number":["25JCQN009"]}]},{"name":"Major Science and Technology Special Project of Henan Province","award":["251100110200"],"award-info":[{"award-number":["251100110200"]}]},{"name":"2025 Annual Key Discipline Construction Project-New Round of Provincial Key Disciplines-Clinical Medicine","award":["15102040X-3-2"],"award-info":[{"award-number":["15102040X-3-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Corneal neovascularization (CNV) is a leading cause of vision loss, but current treatments are limited by poor ocular drug penetration and rapid tear clearance. Luteolin (LUT) is a poorly water-soluble natural anti-angiogenic agent. To address this limitation, we develop an ion- and pH-responsive in situ gel system (LUT-NLC-ISG) by incorporating LUT-loaded nanostructured lipid carriers (LUT-NLC) into a gellan gum\/Carbopol matrix, aiming to enhance ocular bioavailability and therapeutic efficacy against CNV. Methods: LUT-NLC-ISG was optimized using a central composite design-response surface methodology (CCD-RSM) and characterized by physicochemical properties (particle size, viscosity, gelation behavior). Ocular pharmacokinetics and biodistribution were evaluated in rabbits after a single topical administration. Biocompatibility was assessed via Hen\u2019s egg test\u2013chorioallantoic membrane assay (HET-CAM), Draize tests, and cytotoxicity studies. Therapeutic efficacy and mechanism were investigated in a murine model of alkali burn-induced CNV. Results: The optimized LUT-NLC-ISG had a particle size of 25.27 \u00b1 0.23 nm and exhibited a 45-fold viscosity increase upon simulated tear fluid (STF) exposure. In rabbits, LUT-NLC-ISG significantly increased the bioavailability of LUT in ocular tissues compared with LUT-NLC alone, with 2.57-, 1.83-, and 10.59-fold higher area under the concentration\u2013time curve (AUC) in the cornea, conjunctiva, and tears, respectively and exhibited excellent ocular biocompatibility. In the CNV mouse model, 0.1% (w\/v) LUT-NLC-ISG effectively inhibited corneal neovascularization, comparable to 0.025% dexamethasone, and downregulated VEGF-A and MMP-9 expression. Conclusions: LUT-NLC-ISG synergistically combines NLC technology and dual-sensitive in situ gelation to significantly improve LUT ocular bioavailability, offering a promising non-invasive candidate for CNV management.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080908","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:36:13Z","timestamp":1784878573000},"page":"908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ion- and pH-Responsive In Situ Gel Incorporating Luteolin-Loaded Nanostructured Lipid Carriers Enhances Ocular Bioavailability and Anti-Angiogenic Efficacy for Corneal Neovascularization"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3373-9864","authenticated-orcid":false,"given":"Yinjian","family":"Ji","sequence":"first","affiliation":[{"name":"Department of the First Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liang","sequence":"additional","affiliation":[{"name":"Henan Eye Hospital, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Yang","sequence":"additional","affiliation":[{"name":"Henan Eye Hospital, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojuan","family":"Pu","sequence":"additional","affiliation":[{"name":"Henan Eye Hospital, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"He","sequence":"additional","affiliation":[{"name":"Department of the First Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of the First Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of the First Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Henan Eye Hospital, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Henan Eye Hospital, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of the First Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102537","DOI":"10.1016\/j.mtbio.2025.102537","article-title":"From Design to Deployment: The Innovative Role of Nanomicelles in Targeted Ophthalmic Therapeutics","volume":"35","author":"Sun","year":"2025","journal-title":"Mater. 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