Ion- and pH-Responsive In Situ Gel Incorporating Luteolin-Loaded Nanostructured Lipid Carriers Enhances Ocular Bioavailability and Anti-Angiogenic Efficacy for Corneal Neovascularization

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’s egg test–chorioallantoic 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 ± 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–time 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.