Venlafaxine-PLGA nanoparticles provide a fast onset of action in an animal model of depression via nose-to-brain Cayero-Otero, María Dolores Perez-Caballero, Laura Suarez-Pereira, Irene Hidalgo-Figueroa, María Delgado-Sequera, Alejandra Montesinos, Juan Manuel Berrocoso, Esther Martín-Banderas, Lucia Venlafaxine Nose-to-brain PLGA nanoparticles Depression MDC is especially grateful to the V Plan Propio de Investigación from the Vicerrectorado de Investigación (Universidad de Sevilla) for the predoctoral fellowship (grant number USE-CONV-806). Authors are also grateful to the Biology Service of CITIUS for the technical assistance with flow cytometry assays and Microscopy Services of CITIUS for the technical assistance for the technical help with confocal imaging. Authors also thanks funding from Junta de Andalucía (2021/CTS-480; 2019/CTS-480). Background: Current treatment of depression is hindered by the delayed onset of the action of antidepressant drugs, often resulting in treatment failure. Therefore, new therapeutic solutions are imperative. Methodology: Venlafaxine-loaded poly(lactic-co-glycolic acid) nanoparticles were produced by a double emulsion-solvent evaporation method. Cellular safety assessment and internalization assays were carried out in vitro in human olfactory neuroepithelium cells. The antidepressant effect of intranasal (nose-to-brain) nanoparticle administration was assessed in animals submitted to an animal model of depression by behavioral tests, including open-field, sucrose preference test and tail suspension test. Results: The drug entrapment efficiency (55–65 %), particle size (190–210 nm), polydispersity index (<0.2), and zeta potential (−20 mV) of Venlafaxine-loaded poly(lactic-co-glycolic acid) nanoparticles were determined to be adequate. Nanoparticles did not show cytotoxic effects. Cell viability was more than 90 % for all formulations and concentrations assayed. The results of the quantitative and qualitative cell uptake assays were consistent, showing an evident internalization of the nanoparticles into the cells. Furthermore, venlafaxine-loaded nanoparticles administered for just 7 days were able to reverse the phenotype induced by a depressive-like model, showing a significant antidepressant-like effect compared to those treated with free venlafaxine. Conclusions: These findings indicated that intranasal venlafaxine-loaded poly(lactic-coglycolic acid) nanoparticles could become a viable technique for improving venlafaxine brain uptake via nose-to-brain. It could also be a promising nanoplatform for enhancing the treatment of depression. 2025-06-18T07:58:29Z 2025-06-18T07:58:29Z 2025-05-06 journal article M. Dolores Cayero-Otero, Laura Perez-Caballero, Irene Suarez-Pereira, María Hidalgo-Figueroa, Alejandra Delgado-Sequera, Juan Manuel Montesinos, Esther Berrocoso, Lucía Martín-Banderas, Venlafaxine-PLGA nanoparticles provide a fast onset of action in an animal model of depression via nose-to-brain, International Journal of Pharmaceutics, Volume 678, 2025, 125692, ISSN 0378-5173, doi: 10.1016/j.ijpharm.2025.125692 0378-5173 https://hdl.handle.net/10481/104726 10.1016/j.ijpharm.2025.125692 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Elsevier