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Current antifungal agents, limited in number, target specific pathways, but resistance remains a concern. Flucytosine (5FC) exhibits antifungal activity, particularly against <jats:italic>Candida<\/jats:italic>. However, monotherapy efficacy is limited, necessitating combination treatments. Herein, we report PEGylated squalene\u2010based nanocarriers for 5FC loading, aiming to enhance its monotherapy efficacy against <jats:italic>Candida<\/jats:italic> strains. The loading of 5FC within micelles was achieved using the ultrasound\u2010assisted solvent evaporation method. The 5FC\u2010loaded micelles, together with non\u2010loaded micelles, were thoroughly characterized and analyzed. STEM and DLS analysis confirmed the core\u2010shell morphology with nanometric dimensions along with improved colloidal stability. The quantification of drug loading efficiency and drug loading capacity was calculated using the UV\u2010Vis technique. The <jats:italic>in\u2005vitro<\/jats:italic> drug\u2010release studies in simulated physiological conditions showed sustained release within 48\u2005hours. Moreover, the release kinetics calculated using mathematical models showed a Fickian diffusion drug release mechanism in simulated physiological conditions with a slower diffusion rate. The <jats:italic>in\u2005vitro<\/jats:italic> antifungal activity was tested on <jats:italic>Candida albicans<\/jats:italic>, <jats:italic>Candida glabrata<\/jats:italic>, and <jats:italic>Candida parapsilosis<\/jats:italic>. The results showed improved antifungal activity for the nanotherapeutic and unchanged <jats:italic>in\u2005vitro<\/jats:italic> toxicity toward normal cells, suggesting promising advancements in 5FC therapy.<\/jats:p>","DOI":"10.1002\/cmdc.202400432","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T11:30:34Z","timestamp":1725622234000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhancing Flucytosine Anticandidal Activity Using PEGylated Squalene Nanocarrier"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-0088","authenticated-orcid":false,"given":"Bogdan\u2010Florin","family":"Craciun","sequence":"first","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry  41\u2005A Grigore Ghica Voda Alley Iasi 700487 Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-1709","authenticated-orcid":false,"given":"Irina","family":"Rosca","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry  41\u2005A Grigore Ghica Voda Alley Iasi 700487 Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8108-3765","authenticated-orcid":false,"given":"Dragos","family":"Peptanariu","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry  41\u2005A Grigore Ghica Voda Alley Iasi 700487 Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4021-982X","authenticated-orcid":false,"given":"Mariana","family":"Pinteala","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry  41\u2005A Grigore Ghica Voda Alley Iasi 700487 Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2023.08.001"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42770-023-01239-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9120877"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resmic.2021.103915"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0322-2"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011322"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/179663a0"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1968.03150040042009"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222706110"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","unstructured":"N.-H. 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