{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:38Z","timestamp":1787029298018,"version":"build-2736575974"},"reference-count":132,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer\u2019s disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs\/Fb\/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 \u00b1 173 to 668 \u00b1 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle &lt; 90\u00b0), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs\/Fb\/PLA NFs in an AlCl3-induced AD rat model significantly reduced brain-amyloid-\u03b2, phosphorylated tau, IL-1\u03b2, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-\u03b2 (1.78-fold), p-tau (1.42-fold), IL-1\u03b2 (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs\/Fb\/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the A\u03b2\u2013AGER\u2013p-tau axis.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010083","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T14:32:38Z","timestamp":1767882758000},"page":"83","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Repurposing of Empagliflozin-Loaded Buccal Composite (Chitosan\/Silk Fibroin\/Poly(lactic acid)) Nanofibers for Alzheimer\u2019s Disease Management via Modulation of A\u03b2\u2013AGER\u2013p-tau Pathway"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8162-8515","authenticated-orcid":false,"given":"Walaa A.","family":"El-Dakroury","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0980-6006","authenticated-orcid":false,"given":"Samar A.","family":"Salim","sequence":"additional","affiliation":[{"name":"Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El-Sherouk City 11837, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6260-6209","authenticated-orcid":false,"given":"Abdelrahman R.","family":"Said","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-5968","authenticated-orcid":false,"given":"Gihan F.","family":"Asaad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza 12622, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6100-6498","authenticated-orcid":false,"given":"Mohamed F.","family":"Abdelhameed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza 12622, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa E.","family":"Shabana","sequence":"additional","affiliation":[{"name":"Pathology Department, National Research Centre, Dokki, Giza 12622, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara G.","family":"Abualmajd","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidy H.","family":"Mosaad","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaa A.","family":"Salama","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrouk E.","family":"Asran","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayar 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Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102481","DOI":"10.1016\/j.arr.2024.102481","article-title":"Pathogenesis, Diagnostics, and Therapeutics for Alzheimer\u2019s Disease: Breaking the Memory Barrier","volume":"101","author":"Kamatham","year":"2024","journal-title":"Ageing Res. 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