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Nanostructured lipid carriers (NLCs) have been proposed as delivery platforms capable of modulating interfacial interactions and improving mucosal transport. This study aimed to quantitatively evaluate the ex vivo buccal permeation of angiotensin II (Ang II), used as a hydrophilic peptide model, when associated with NLCs compared with free peptide under matched Franz diffusion cell conditions. Methods: Ang II-associated NLCs were prepared by melt emulsification combined with a low-energy injection technique. Particle size, polydispersity index, and zeta potential were determined by dynamic light scattering and laser Doppler electrophoresis. Association efficiency and drug loading were quantified by indirect spectrofluorometric analysis. Ex vivo permeation studies were conducted using porcine buccal mucosa mounted in Franz diffusion cells, and cumulative permeation, steady-state flux, and apparent permeability coefficients were calculated. Results: The NLCs exhibited nanometric size, moderate polydispersity, and association efficiency above 80%, and remained colloidally stable at 4 \u00b0C for 28 days. In ex vivo experiments, Ang II-associated NLCs showed measurable cumulative permeation, reaching approximately 9% after 2 h, whereas free Ang II was not detected in the receptor compartment under the tested conditions. Conclusions: This work provides a quantitative ex vivo buccal transport comparison of a hydrophilic peptide model delivered as NLC-associated versus free peptide under matched Franz cell conditions. The findings support further investigation of NLC-based approaches for buccal delivery of vasoactive peptides and provide a rational basis for future in vivo evaluation of mucosal delivery performance and systemic exposure.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040416","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ex Vivo Buccal Permeability of Nanostructured Lipid Carriers (NLCs) Associated with a Peptide Drug Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6849-4120","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Vargas-Valderrama","sequence":"first","affiliation":[{"name":"Drug Delivery Lab, Department of Pharmaceutic Science and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380494, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-2168","authenticated-orcid":false,"given":"Javier O.","family":"Morales","sequence":"additional","affiliation":[{"name":"Drug Delivery Lab, Department of Pharmaceutic Science and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380494, Chile"},{"name":"Advanced Center for Chronic Diseases, ACCDiS, Santiago 8380494, Chile"},{"name":"Center of New Drugs for Hypertension and Heart Failure (CENDHY), Santiago 8380494, Chile"},{"name":"Nanocarrier Advanced Inhalation Research Center, NanoAIR, Santiago 8380494, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"ref_1","unstructured":"(2026, February 23). 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