{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:29:23Z","timestamp":1791944963808,"version":"4.3.4"},"reference-count":92,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Ha\u2019il, Saudi Arabia","award":["RG-23 126"],"award-info":[{"award-number":["RG-23 126"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Parkinson\u2019s disease (PD) is a progressive neuro-degenerative disorder characterized by \u03b1-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce \u03b1-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), a monoamine oxidase-B (MAO-B) inhibitor, has low bioavailability, restricting its effectiveness. This study aims to develop an intranasal (IN) albumin-coated liposomal system (C-LipSel-siSNCA2) for the co-delivery of Sel and \u03b1-synuclein-targeting siRNA (siSNCA2) to enhance brain targeting and therapeutic efficacy. Methods: Liposomes were prepared using the ethanol injection method and optimized via D-optimal design for size, charge, and encapsulation efficiency (EE%). The optimized formulation was coated with human serum albumin (HSA) and characterized for stability, cellular uptake, and gene silencing. In vivo pharmacokinetics and pharmacodynamics were assessed in a rotenone-induced PD rat model to evaluate the motor function, biochemical markers, and brain-targeting efficiency. Results: Optimized liposomes had a particle size of 113.5 \u00b1 6.8 nm, zeta potential of 6.2 \u00b1 0.8 mV, and high EE% (Sel: 92.35%; siRNA: 78.66%). Albumin coating increased size to 136.5 \u00b1 10.3 nm and shifted zeta potential to \u221213.5 \u00b1 1.4 mV, enhancing stability and targeting. IN administration achieved a 3-fold increase in brain area under the concentration-time curve (AUC) versus intravenous delivery. In PD rats, C-LipSel-siSNCA2 improved motor and non-motor functions, restored dopamine levels, enhanced catalase activity, and reduced MAO-B levels, mitigating dopamine degradation and \u03b1-synuclein aggregation. Conclusions: This non-invasive, dual-action nanoplatform offers a targeted therapy for PD, combining siRNA gene silencing and MAO-B inhibition, with the potential for clinical translation in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020243","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T08:05:42Z","timestamp":1739347542000},"page":"243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tailored Intranasal Albumin Caged Selegiline-\u03b1 Synuclein siRNA Liposome with Improved Efficiency in Parkinson\u2019s Model"],"prefix":"10.3390","volume":"17","author":[{"given":"Ahmed A.","family":"Katamesh","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 81442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hend Mohamed","family":"Abdel-Bar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, University of Sadat City, Menoufia P.O. Box 32897, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6031-4154","authenticated-orcid":false,"given":"Mohammed Khaled Bin","family":"Break","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 81442, Saudi Arabia"},{"name":"Medical and Diagnostic Research Centre, University of Ha\u2019il, Ha\u2019il 55473, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2412-4345","authenticated-orcid":false,"given":"Shimaa M.","family":"Hassoun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 81442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-7786","authenticated-orcid":false,"given":"Gehad Mohammed","family":"Subaiea","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 81442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5567-6708","authenticated-orcid":false,"given":"Amr","family":"Radwan","sequence":"additional","affiliation":[{"name":"Research Department, Academy of Scientific Research and Technology, Cairo 11694, Egypt"},{"name":"Egyptian Center for Innovation and Technology Development, Cairo 11512, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2030-4231","authenticated-orcid":false,"given":"Hadel A.","family":"Abo El-Enin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Egyptian Drug Authority, Giza 12511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"ref_1","first-page":"S3","article-title":"The emerging evidence of the Parkinson pandemic","volume":"8","author":"Dorsey","year":"2018","journal-title":"J. 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