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Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus\u00ae-based nanomicelles (NMs) loaded with EFV (10 mg\/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus\u00ae NMs increased the drug\u2019s apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 \u00b0C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2\u20137.5 and its storage micellar physicochemical stability at 4 \u00b0C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI &gt; 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020241","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T08:05:42Z","timestamp":1739347542000},"page":"241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Efavirenz Repurposing Challenges: A Novel Nanomicelle-Based Antiviral Therapy Against Mosquito-Borne Flaviviruses"],"prefix":"10.3390","volume":"17","author":[{"given":"Sof\u00eda","family":"Maldonado","sequence":"first","affiliation":[{"name":"Departamento de Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Fuentes","sequence":"additional","affiliation":[{"name":"Departamento de Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezequiel","family":"Bernabeu","sequence":"additional","affiliation":[{"name":"Departamento de Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Facundo","family":"Bertera","sequence":"additional","affiliation":[{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Departamento de Farmacolog\u00eda, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Opezzo","sequence":"additional","affiliation":[{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Departamento de Farmacolog\u00eda, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Lagomarsino","sequence":"additional","affiliation":[{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Departamento de Farmacia Cl\u00ednica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4008-7273","authenticated-orcid":false,"given":"Fleming","family":"Mart\u00ednez Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Grupo de Investigaciones Farmac\u00e9utico-Fisicoqu\u00edmicas, Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia, Sede Bogot\u00e1, Bogot\u00e1 111321, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo R.","family":"Choi","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), CONICET, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jimena","family":"Salgueiro","sequence":"additional","affiliation":[{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Departamento de Fisicomatem\u00e1tica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa B.","family":"Damonte","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8992-9841","authenticated-orcid":false,"given":"Christian","family":"H\u00f6cht","sequence":"additional","affiliation":[{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Departamento de Farmacolog\u00eda, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela A.","family":"Moretton","sequence":"additional","affiliation":[{"name":"Departamento de Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2356-6624","authenticated-orcid":false,"given":"Claudia S.","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego A.","family":"Chiappetta","sequence":"additional","affiliation":[{"name":"Departamento de Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Instituto de Tecnolog\u00eda Farmac\u00e9utica y Biofarmacia (InTecFyB), Universidad de Buenos Aires, Buenos Aires CP1113, Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires CP1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2025, January 03). 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