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

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. The 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 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 the 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.