Enhanced Blood-Brain Barrier Penetrability of BACE1 SiRNA-Loaded
Prussian Blue Nanocomplexes for Alzheimer's Disease Synergy Therapy
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.