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Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP\/Don@BSA (RDB), was developed to enable effective AD therapy via a \u201ccocktail strategy\u201d. Utilizing bovine serum albumin (BSA), the system crosses the blood\u2013brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP\/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.<\/jats:p>","DOI":"10.1021\/acsami.6c05393","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T16:52:00Z","timestamp":1783961520000},"page":"39739-39756","source":"Crossref","is-referenced-by-count":1,"title":["A Multitarget Nanosystem\nLoaded with Donepezil for\nAlzheimer\u2019s Disease Treatment by Activating Mitophagy and Reshaping\nthe Inflammatory Microenvironment"],"prefix":"10.1021","volume":"18","author":[{"given":"Liqiang","family":"Wang","sequence":"first","affiliation":[{"name":"Shenzhen Longhua Maternity and Child Healthcare Hospital , ,","place":["Shenzhen, China, 518110"]},{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyu","family":"Cai","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglan","family":"Yang","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Liu","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyao","family":"Wu","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2237-9309","authenticated-orcid":true,"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen Longhua Maternity and Child Healthcare Hospital , ,","place":["Shenzhen, China, 518110"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"2026072908071259400_cit1","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/S1474-4422(10)70119-8","article-title":"Alzheimer\u2019s\nDisease: Clinical Trials and Drug Development","volume":"9","author":"Mangialasche","year":"2010","journal-title":"Lancet Neurol"},{"key":"2026072908071259400_cit2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202101462","article-title":"Modeling Sporadic\nAlzheimer\u2019s Disease in Human Brain Organoids under Serum Exposure","volume":"8","author":"Chen","year":"2021","journal-title":"Adv. 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