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This limitation is particularly critical for hydrophilic and high-molecular-weight (HMW) therapeutics such as proteins and biologics. In this study, we investigated transcorneal iontophoresis as a strategy to enhance the delivery of HMW compounds using albumin (66\u00a0kDa) as a model macromolecule. Ex vivo rabbit corneas were exposed to iontophoretic currents ranging from 0.5 to 7\u00a0mA for clinically relevant conditions, while an extreme non-clinical current (500\u00a0mA) was included as a destructive positive control to model irreversible tissue disruption. Albumin permeation was quantified by intrinsic fluorescence spectroscopy, and corneal structural responses were assessed using Fourier-transform infrared (FTIR) spectroscopy. In parallel, computational thermal modeling based on the Pennes bioheat equation was employed to evaluate current-dependent Joule heating and thermal safety margins. Results demonstrated that iontophoresis significantly enhanced albumin transport compared with passive diffusion, with increased permeation at higher currents, particularly at 6\u20137\u00a0mA. Thermal simulations indicated that currents\u2009\u2264\u20092\u00a0mA maintained corneal surface temperature within the normal physiological range (32\u201336\u00a0\u00b0C), while currents\u2009\u2265\u20093\u00a0mA progressively increased corneal temperature, approaching established thermal stress thresholds depending on exposure time. FTIR analysis revealed current-dependent spectral alterations consistent with changes in hydration dynamics, protein conformational environment, and lipid organization, suggesting reversible molecular adaptation at low-to-moderate currents and pronounced disruption at extreme electrical exposure. Collectively, this study identifies a practical current-time operational window for transcorneal iontophoresis that enhances macromolecular transport while maintaining corneal thermal and molecular integrity, supporting its potential for non-invasive ocular delivery of biologic therapeutics.<\/jats:p>","DOI":"10.1038\/s41598-026-43580-y","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:37:43Z","timestamp":1774964263000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ex vivo and computational investigation of corneal iontophoresis to enhance penetration of high-molecular-weight compounds: a study using albumin as a model molecule"],"prefix":"10.1038","volume":"16","author":[{"given":"Asmaa K.","family":"Mohamed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif S.","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaimaa M.","family":"Elshibly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehan M.","family":"Kamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"43580_CR1","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.preteyeres.2010.08.002","volume":"29","author":"Y Diebold","year":"2010","unstructured":"Diebold, Y. & Calonge, M. 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