{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:52:48Z","timestamp":1787579568753,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"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: Dementia remains one of the major global health challenges of the modern era. Researchers worldwide continue to seek effective therapeutic strategies to combat this neurodegenerative condition. Silymarin is a natural compound with strong neuroprotective and antioxidant properties that holds great potential for dementia management; however, its poor aqueous solubility and limited ability to cross the blood\u2013brain barrier (BBB) have restricted its clinical application. This study focused on the formulation and evaluation of a heparin\u2013pullulan silymarin liposomal (HPSL) nano-gel to enhance the neuroprotective efficacy of silymarin, with potential for improved brain targeting effects. Methods: The HPSL nano-gel was synthesized using the thin-film hydration technique and optimized based on entrapment efficiency, particle size distribution, zeta potential, and in vitro release kinetics. The neuroprotective efficacy of the HPSL nano-gel was evaluated in mice using behavioral evaluations, biochemical quantification of oxidative stress markers, evaluation of cholinergic enzyme activity and detailed histopathological examination of brain tissues. Results: Morphological characterization using scanning electron microscopy (SEM) confirmed a uniform nano-scale structure. The optimized formulation (HPSL-3) exhibited a particle size of 406.07 \u00b1 19.33 nm, zeta potential of \u221223.72 \u00b1 7.64 mV and an entrapment efficiency of 73.53 \u00b1 12.05%, indicating good colloidal stability and efficient drug loading. The in vitro release profile followed non-Fickian diffusion kinetics, suggesting sustained drug release behavior. Behavioral studies in scopolamine-induced amnesic mice (elevated plus maze, hole board, and light\/dark paradigms) demonstrated significant (p \u2264 0.001) improvements in learning and memory retention. Biochemical analyses showed increased levels of ChAT, SOD, CAT, and GSH, along with decreased AChE and MDA levels, supporting the neuroprotective potential of the formulation. Histopathological evaluation revealed marked attenuation of neuronal degeneration, inflammation, and edema (HAI = 4) compared to the scopolamine-treated group (HAI = 11). Conclusions: Overall, the HPSL-2 formulation effectively enhanced silymarin delivery across the BBB, demonstrating potent antioxidant, neuroprotective, and cholinergic modulatory effects. These findings suggest that HPSL-2 represents a promising nano-carrier system for the management of dementia and other oxidative-stress-related neurological disorders.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030348","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T11:44:52Z","timestamp":1773229492000},"page":"348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and Characterization of Heparin\u2013Pullulan Liposomal Nano-Gel for Enhanced Silymarin Delivery in Dementia Therapy: In Vivo Evaluation in Albino Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0959-0989","authenticated-orcid":false,"given":"Aamir","family":"Mushtaq","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Government College University Lahore, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-5235","authenticated-orcid":false,"given":"Hamid Saeed","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences Lahore, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3526-4132","authenticated-orcid":false,"given":"Sairah Hafeez","family":"Kamran","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4113-3067","authenticated-orcid":false,"given":"Umar Farooq","family":"Gohar","sequence":"additional","affiliation":[{"name":"Institute of Industrial Biotechnology, Government College University Lahore, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Daniefla","family":"Neculoiu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petru Cezario","family":"Podasca","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2442-6917","authenticated-orcid":false,"given":"Marius Alexandru","family":"Moga","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrada Camelia","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103576","DOI":"10.1016\/j.ijnurstu.2020.103576","article-title":"Advance care planning for people living with dementia: An umbrella review of effectiveness and experiences","volume":"107","author":"Bunn","year":"2020","journal-title":"Int. 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