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Impaired A\u03b2 clearance across the blood\u2013brain barrier (BBB) is a key contributor to AD pathogenesis. Two sequential barriers to A\u03b2 clearance are identified: proprotein convertase subtilisin\/kexin type 9 (PCSK9) upregulation in cerebrovascular endothelial cells compromises low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1)\u2010mediated A\u03b2 efflux, whereas increased intracellular A\u03b2 handling after PCSK9 silencing induces tribbles pseudokinase 3 (TRIB3) upregulation and exposes an autophagy blockade restricting intracellular A\u03b2 degradation. PCSK9 silencing restores LRP1 expression and enhances A\u03b2 uptake and efflux, whereas TRIB3 knockdown restores autophagic flux and facilitates A\u03b2 degradation. SITR (siPCSK9\/siTRIB3@TPN\u2010RAP), a RAP\u2010modified siRNA nanodelivery system based on tea polyphenol nanoparticles (TPNs), enables brain\u2010enriched co\u2010delivery of siPCSK9 and siTRIB3. SITR enhances BBB penetration and preferentially accumulates in cerebrovascular endothelial cells and microglia. In APP\/PS1 mice, SITR improves cognitive performance, reduces A\u03b2 and cerebral amyloid angiopathy burden, preserves vascular and neuronal homeostasis, and suppresses neuroinflammation, while showing no overt short\u2010term systemic toxicity under a 6\u2010week regimen. These findings establish PCSK9 and TRIB3 as complementary therapeutic targets and support SITR as an effective nanoplatform integrating enhanced A\u03b2 efflux with restored autophagic degradation for AD intervention.<\/jats:p>","DOI":"10.1002\/advs.77929","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:39:26Z","timestamp":1790743166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restores A\u03b2 Clearance by Overcoming PCSK9\u2013LRP1 Dysregulation and TRIB3\u2010Mediated Autophagy Blockade in Alzheimer's Disease"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-3157","authenticated-orcid":false,"given":"Jie","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Neurology First Hospital of Shanxi Medical University  Taiyuan Shanxi China"},{"name":"The First Clinical Medical School of Shanxi Medical University  Taiyuan 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