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A\u03b2 generation was highly regulated by beta\u2010site amyloid precursor protein cleaving enzyme 1 (BACE1), which is a prime drug target for AD therapy. The silence of BACE1 function to slow down A\u03b2 production was accepted as an effective strategy for combating AD. Herein, BACE1 interfering RNA, metallothionein (MT) and ruthenium complexes ([Ru(bpy)<jats:sub>2<\/jats:sub>dppz]<jats:sup>2+<\/jats:sup>) were all loaded in Prussian blue nanoparticles (PRM\u2010siRNA). PRM\u2010siRNA under near\u2010infrared light irradiation showed good photothermal effect and triggered instantaneous opening of blood\u2010brain barrier (BBB) for enhanced drug delivery. BACE1 siRNA slowed down A\u03b2 production and Cu<jats:sup>2+<\/jats:sup> chelation by metallothionein (MT) synergistically inhibited A\u03b2 aggregation. Ruthenium (Ru) could real\u2010timely track A\u03b2 degradation and aggregation. The results indicated that PRM\u2010siRNA significantly blocked A\u03b2 aggregation and attenuated A\u03b2\u2010induced neurotoxicity and apoptosis in vitro by inhibiting ROS\u2010mediated oxidative damage and mitochondrial dysfunction through regulating the Bcl\u20102 family. PRM\u2010siRNA in vivo effectively improved APP\/PS1 mice learning and memory by alleviating neural loss, neurofibrillary tangles and activation of astrocytes and microglial cells in APP\/PS1 mice by inhibiting BACE1, oxidative damage and tau phosphorylation. Taken together, our findings validated that BACE1 siRNA\u2010loaded Prussian blue nanocomplexes showed enhanced BBB penetrability and AD synergy therapy.<\/jats:p>","DOI":"10.1002\/exp.20230178","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T20:57:34Z","timestamp":1741726654000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Enhanced Blood\u2010Brain Barrier Penetrability of BACE1 SiRNA\u2010Loaded Prussian Blue Nanocomplexes for Alzheimer's Disease Synergy Therapy"],"prefix":"10.1002","volume":"5","author":[{"given":"Xiaoyuan","family":"Ding","sequence":"first","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"},{"name":"College of Biotechnology and Pharmaceutical Engineering West Anhui University  Luan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyu","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Feng","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Medical and Health Lab of Brain Injury and Functional Rehabilitation The Second Affiliated Hospital of Shandong First Medical University  Taian Shandong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zekun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qile","family":"Song","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Medical and Health Lab of Brain Injury and Functional Rehabilitation The Second Affiliated Hospital of Shandong First Medical University  Taian Shandong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxue","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bangjia","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Fu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Medical and Health Lab of Brain Injury and Functional Rehabilitation The Second Affiliated Hospital of Shandong First Medical University  Taian Shandong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4485-1344","authenticated-orcid":false,"given":"Cundong","family":"Fan","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Medical and Health Lab of Brain Injury and Functional Rehabilitation The Second Affiliated Hospital of Shandong First Medical University  Taian Shandong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10989-006-9012-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11434-009-0065-y"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/208641"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1071\/CH09454"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1515\/revneuro-2019-0052"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0488028"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6TB01215A"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20141168"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2021.111591"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313572200"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05061.x"},{"key":"e_1_2_9_13_1","first-page":"830","article-title":"Advancements in BACE1 and Non\u2010Peptide BACE1 Inhibitors for Alzheimer's Disease","volume":"57","author":"Shah N. 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