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Being serotonin receptor antagonist, AGO is orally administered for depression treatment. Here in, AGO was used for intraocular pressure management due to its agonistic activity on the melatonin receptors in the eyes. AGO is a BCS II drug, with low oral bioavailability and massive first-pass metabolism. Oleic acid enriched leciplexes were investigated as novel mucoadhesive cationic nanocarriers to improve AGO\u2019s ocular bioavailability and prolong its pharmacological effect. Twenty-four AGO loaded leciplexes were fabricated by single-step procedure. AGO: lipid ratio, surfactant: phosphatidyl choline ratio, cationic surfactant type, permeation enhancer type were investigated. For optimization; in-vitro assessment of size, homogeneity, surface charge, drug entrapment and in-vitro release was conducted. The optimum system was further examined for crystallinity, compatibility, morphology, pH, refractive index, surface tension and stability. L20 developed at a drug: lipid ratio of 1: 20, cetyltrimethylammonium bromide and phosphatidyl choline at a ratio of 1:5 respectively and 0.25% w\/v oleic acid was the optimum system with respect to shape and PS (spherical, 491\u00a0nm), PDI (0.29), ZP (31.1\u00a0mV), EE (81.8%), in-vitro release (Q\n                    <jats:sub>2h<\/jats:sub>\n                    ; 34.9%, Q\n                    <jats:sub>8h<\/jats:sub>\n                    ; 91.2%), crystallinity, pH (6.3), refractive index (1.24), surface tension (46.2 mN\/m) and stability. AGO pharmacodynamic and histopathological studies were conducted in rabbits. Compared to AGO dispersion, elevated maximum IOP reduction (74.2%), prolonged mean residence time (12.88 h), enhanced bioavailability (3 folds) and normal histopathological micrographs proved the potential of L20 leciplex in improving and sustaining the ocular bioavailability of AGO and maintaining its safety.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1208\/s12249-025-03250-0","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T17:03:03Z","timestamp":1761325383000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Oleic acid Enriched Leciplexes as Novel Mucoadhesive Cationic Nanocarriers of Agomelatine for Glaucoma Treatment"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8830-6781","authenticated-orcid":false,"given":"Mai Ahmed","family":"Tawfik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-9502","authenticated-orcid":false,"given":"Sadek","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-3840","authenticated-orcid":false,"given":"Rania Moataz","family":"El-Dahmy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3545-921X","authenticated-orcid":false,"given":"Diana E.","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"3250_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ijpharm.2019.01.070","volume":"560","author":"WH Abd-Elsalam","year":"2019","unstructured":"Abd-Elsalam WH, ElKasabgy NA. Mucoadhesive olaminosomes: a novel prolonged release nanocarrier of agomelatine for the treatment of ocular hypertension. Int J Pharm. 2019;560:235\u201345. https:\/\/doi.org\/10.1016\/j.ijpharm.2019.01.070.","journal-title":"Int J Pharm"},{"issue":"6","key":"3250_CR2","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1080\/02652048.2023.2215326","volume":"40","author":"AA Nemr","year":"2023","unstructured":"Nemr AA, El-Mahrouk GM, Badie HA. Enhancement of ocular anti-glaucomic activity of agomelatine through fabrication of hyaluronic acid modified-elastosomes: formulation, statistical optimisation, in vitro characterisation, histopathological study, and in vivo assessment. 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