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Enhanced Blood-Brain Barrier Penetrability of BACE1 SiRNA-Loaded Prussian Blue Nanocomplexes for Alzheimer's Disease Synergy Therapy
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  • Xiaoyuan Ding,
  • Yanyu Hu,
  • Zekun Wang,
  • Xiaotong Feng,
  • Qile Song,
  • Chunxue Dai,
  • Bangjia Yang,
  • Xiaoyan Fu,
  • Dongdong Sun,
  • Cun-dong Fan
Xiaoyuan Ding
Anhui Agricultural University
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Yanyu Hu
Anhui Agricultural University
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Zekun Wang
Anhui Agricultural University
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Xiaotong Feng
Shandong First Medical University
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Qile Song
Shandong First Medical University
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Chunxue Dai
Anhui Agricultural University
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Bangjia Yang
Anhui Agricultural University
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Xiaoyan Fu
Shandong First Medical University
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Dongdong Sun
Anhui Agricultural University
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Cun-dong Fan
Shandong First Medical University

Corresponding Author:[email protected]

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Abstract

Amyloid-β (Aβ) deposition was an important pathomechanisms of Alzheimer’s disease (AD). Aβ generation was highly regulated by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is a prime drug target for AD therapy. Silence of BACE1 function to slow down Aβ production was accepted as an effective strategy for combating AD. Herein, BACE1 interfering RNA, metallothionein (MT) and ruthenium complexes ([Ru(bpy)2dppz]2+) were all loaded in prussian blue nanoparticles (PRM-siRNA). PRM-siRNA under near-infrared light (NIR) irradiation showed good photothermal effect and triggered instantaneous opening of blood-brain barrier (BBB) for enhanced drug delivery. BACE1 siRNA slowed down Aβ production and Cu2+ chelation by metallothionein (MT) synergistically inhibited Aβ aggregation. Ruthenium (Ru) could real-timely track Aβ degradation and aggregation. The results indicated that PRM-siRNA significantly blocked Aβ aggregation, and attenuated Aβ-induced neurotoxicity and apoptosis in vitro by inhibiting ROS-mediated oxidative damage and mitochondrial dysfunction through regulating Bcl-2 family. PRM-siRNA 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-loaded prussian blue nanocomplexes showed enhanced BBB penetrability and AD synergy therapy.
29 Jan 20241st Revision Received
01 Feb 2024Assigned to Editor
01 Feb 2024Submission Checks Completed
01 Feb 2024Reviewer(s) Assigned
12 Feb 2024Review(s) Completed, Editorial Evaluation Pending