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The purpose of this project was to create fenchone-augmented novasomes to enhance the trans-tympanic penetration of levofloxacin (LFX) and improve its antibacterial efficacy. Novasomes were formulated using the ethanol injection technique and optimized using a 2\n                    <jats:sup>3<\/jats:sup>\n                    factorial design. The factors analyzed included the stearic acid to drug ratio (A), cholesterol to fenchone ratio (B), and surfactant concentration (%) (C). The optimization feature of Design-Expert\u00ae software was utilized to identify the optimal formulation by minimizing particle size (PS) and poly-dispersity index (PDI) while maximizing entrapment efficiency (EE%) and the absolute value of the zeta potential (ZP). The best formulation achieved a desirability of 0.964, with an EE% of 73.39%, a PS of 179.25\u00a0nm, and a ZP of\u2009\u2212\u200931.95\u00a0mV. The formulation will be subjected to additional evaluations, including in vitro, ex vivo, microbiological, and in vivo testing. A thorough in vitro analysis revealed a biphasic release profile, significant stability, and a spherical morphology. Novasomes exhibited greater ex vivo permeation and superior flux values compared to the LFX solution. The optimum formula demonstrated high otic tolerance. The optimized formula demonstrated markedly enhanced antibacterial activity, with significantly lower minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    and\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    compared to the drug solution. Moreover, it exhibited superior biofilm inhibition, even at sub-MIC concentrations, underscoring its efficacy. These findings highlight the potential of LFX-loaded novasomes as an efficient non-invasive method for managing middle ear infections.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04659-x","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T04:11:08Z","timestamp":1763352668000},"page":"5969-5986","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Terpene-augmented novasomal carriers for trans-tympanic drug delivery: a comprehensive optimization and in vivo evaluation"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-9502","authenticated-orcid":false,"given":"Sadek","family":"Ahmed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Fayez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Attia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa Ahmed","family":"El-Setouhy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"4659_CR1","doi-asserted-by":"publisher","first-page":"6249","DOI":"10.2147\/IJN.S319348","volume":"16","author":"MA Abdelbari","year":"2021","unstructured":"Abdelbari MA, El-Mancy SS, Elshafeey AH, Abdelbary AA (2021) Implementing spanlastics for improving the ocular delivery of clotrimazole: in vitro characterization, ex vivo permeability, microbiological assessment and in vivo safety study. 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