Restores Aβ Clearance by Overcoming PCSK9–LRP1 Dysregulation and TRIB3‐Mediated Autophagy Blockade in Alzheimer's Disease

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, and vascular dysfunction, yet effective therapies remain limited. Impaired Aβ clearance across the blood-brain barrier (BBB) is a key contributor to AD pathogenesis. Two sequential barriers to Aβ clearance are identified: proprotein convertase subtilisin/kexin type 9 (PCSK9) upregulation in cerebrovascular endothelial cells compromises low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux, whereas increased intracellular Aβ handling after PCSK9 silencing induces tribbles pseudokinase 3 (TRIB3) upregulation and exposes an autophagy blockade restricting intracellular Aβ degradation. PCSK9 silencing restores LRP1 expression and enhances Aβ uptake and efflux, whereas TRIB3 knockdown restores autophagic flux and facilitates Aβ degradation. SITR (siPCSK9/siTRIB3@TPN-RAP), a RAP-modified siRNA nanodelivery system based on tea polyphenol nanoparticles (TPNs), enables brain-enriched co-delivery 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 Aβ and cerebral amyloid angiopathy burden, preserves vascular and neuronal homeostasis, and suppresses neuroinflammation, while showing no overt short-term systemic toxicity under a 6-week regimen. These findings establish PCSK9 and TRIB3 as complementary therapeutic targets and support SITR as an effective nanoplatform integrating enhanced Aβ efflux with restored autophagic degradation for AD intervention.