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Oleuropein (Ole), a phenolic compound with proven anti-inflammatory properties, suffers from poor aqueous stability and limited oral bioavailability, constraining its clinical application. To overcome these limitations, we developed and optimized chitosan (CS)-coated liposomes for oral delivery of Ole. Using a Box-Behnken design, the optimized formulation exhibited a particle size of 168.73 \u00b1 3.86 nm, a polydispersity index (PDI) of 0.17 \u00b1 0.01, a moderate negative zeta potential (\u221222.50 \u00b1 2.39 mV), an encapsulation efficiency of 87.17 \u00b1 0.27%, and a loading capacity of 12.22 \u00b1 0.25%. The CS-coated formulation retained acceptable colloidal stability under refrigerated storage, enabled pH-responsive sustained release governed by Fickian diffusion, and enhanced endothelial nanocarrier uptake in EA.hy926 cells. The formulation was well tolerated in vitro, with cell viability exceeding 90% across a 500\u20134000 ng\/mL concentration range. In a TNF-\u03b1-induced murine model of acute vascular inflammation, daily oral administration of CS-Ole-Lip (20 mg\/kg) significantly suppressed serum IL-6 by 6.90-fold (p &amp;lt; 0.05) and MCP-1 by 2.45-fold relative to TNF-\u03b1 controls (p &amp;lt; 0.0001), with numerically greater suppression than that observed with free Ole and uncoated Ole-Lip at the same dose. CS-Ole-Lip at 2 mg\/kg, one-tenth of the 20 mg\/kg dose evaluated in this study, produced substantial serum cytokine suppression, suggesting a potential dose-sparing effect. No treatment-associated elevations in the evaluated serum markers of hepatic or renal function or overt histological abnormalities in the examined organs were observed. These findings support CS-Ole-Lip as a stable oral nanocarrier with enhanced anti-inflammatory pharmacodynamic activity. The mechanistic basis for the dose-sparing effect requires direct pharmacokinetic and molecular validation.<\/jats:p>","DOI":"10.1021\/acsomega.6c06263","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:02:07Z","timestamp":1790218927000},"page":"59668-59685","source":"Crossref","is-referenced-by-count":0,"title":["Chitosan-Coated Oleuropein Nanoliposomes Enable Dose-Sparing\nSuppression of Serum Inflammatory Markers in a TNF-\u03b1-Induced\nVascular Inflammation Model"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4754-5505","authenticated-orcid":true,"given":"Roi Martin B.","family":"Pajimna","sequence":"first","affiliation":[{"name":"University of Santo Tomas , , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , ,","place":["Manila, Philippines, 1015"]},{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3548-4562","authenticated-orcid":true,"given":"John Wilfred T.","family":"Malabanan","sequence":"additional","affiliation":[{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]},{"name":"Trinity University of Asia , , ,","place":["Quezon City, Philippines, 1102"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonthaneth","family":"Nalinratana","sequence":"additional","affiliation":[{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]},{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Song","sequence":"additional","affiliation":[{"name":"Shenyang Pharmaceutical University , , , ,","place":["Shenyang, Liaoning, China, 110016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4088-6542","authenticated-orcid":true,"given":"Pranee","family":"Rojsitthisak","sequence":"additional","affiliation":[{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]},{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1391-6993","authenticated-orcid":true,"given":"Pornchai","family":"Rojsitthisak","sequence":"additional","affiliation":[{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]},{"name":"Chulalongkorn University , , ,","place":["Bangkok, Thailand, 10330"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes L.","family":"Llamasares-Castillo","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , ,","place":["Manila, Philippines, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"11","key":"2026100610465165600_cit1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-07166-8","article-title":"Inflammation in atherosclerosis:\npathophysiology and mechanisms","volume":"15","author":"Ajoolabady","year":"2024","journal-title":"Cell Death Dis."},{"issue":"1","key":"2026100610465165600_cit2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7092151","article-title":"Vascular Inflammation and Oxidative\nStress: Major Triggers for Cardiovascular Disease","volume":"2019","author":"Steven","year":"2019","journal-title":"Oxid. 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Sci."},{"issue":"1","key":"2026100610465165600_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00955-7","article-title":"Inflammation and atherosclerosis:\nsignaling pathways and therapeutic\nintervention","volume":"7","author":"Kong","year":"2022","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026100610465165600_cit5","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10071044","article-title":"Olive Polyphenols: Antioxidant and\nAnti-Inflammatory\nProperties","volume":"10","author":"Bucciantini","year":"2021","journal-title":"Antioxidants"},{"key":"2026100610465165600_cit6","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8120578","article-title":"Oleuropein, a Bioactive\nCompound from Olea europaea L., as a Potential Preventive and Therapeutic\nAgent in Non-Communicable Diseases","volume":"8","author":"Nediani","year":"2019","journal-title":"Antioxidants"},{"key":"2026100610465165600_cit7","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13091040","article-title":"Systemic Health\nEffects of Oleuropein and Hydroxytyrosol Supplementation: A Systematic\nReview of Randomized Controlled Trials","volume":"13","author":"Frumuzachi","year":"2024","journal-title":"Antioxidants"},{"key":"2026100610465165600_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2025.143877","article-title":"Proniosomal encapsulation of olive\nleaf extract for improved delivery\nof oleuropein: Towards the valorization of an agro-industrial byproduct","volume":"479","author":"Ilgaz","year":"2025","journal-title":"Food Chem."},{"issue":"1","key":"2026100610465165600_cit9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.34172\/apb.2023.009","article-title":"What We Need\nto Know about Liposomes\nas Drug Nanocarriers: An Updated Review","volume":"13","author":"Abbasi","year":"2023","journal-title":"Adv.\nPharm. 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