Ding Xiaoyuan, Hu Yanyu, Feng Xiaotong, Wang Zekun, Song Qile, Dai Chunxue, Yang Bangjia, Fu Xiaoyan, Sun Dongdong, Fan Cundong
School of Life Sciences Anhui Agricultural University Hefei China.
College of Biotechnology and Pharmaceutical Engineering West Anhui University Luan China.
Exploration (Beijing). 2025 Mar 7;5(4):e20230178. doi: 10.1002/EXP.20230178. eCollection 2025 Aug.
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)dppz]) 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 Cu 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.
淀粉样蛋白-β（Aβ）沉积是阿尔茨海默病（AD）的重要发病机制。Aβ的产生受到β-位点淀粉样前体蛋白裂解酶1（BACE1）的高度调控，BACE1是AD治疗的主要药物靶点。沉默BACE1功能以减缓Aβ产生被认为是对抗AD的有效策略。在此，BACE1干扰RNA、金属硫蛋白（MT）和钌配合物（[Ru(bpy)dppz]）都负载于普鲁士蓝纳米颗粒（PRM-siRNA）中。PRM-siRNA在近红外光照射下显示出良好的光热效应，并触发血脑屏障（BBB）瞬间开放以增强药物递送。BACE1 siRNA减缓Aβ产生，金属硫蛋白（MT）的铜螯合作用协同抑制Aβ聚集。钌（Ru）能够实时追踪Aβ的降解和聚集。结果表明，PRM-siRNA通过调节Bcl-2家族抑制ROS介导氧化损伤和线粒体功能障碍，在体外显著阻断Aβ聚集并减轻Aβ诱导的神经毒性和细胞凋亡。PRM-siRNA在体内通过抑制BACE1、氧化损伤和tau磷酸化，减轻APP/PS1小鼠的神经细胞丢失、神经纤维缠结以及星形胶质细胞和小胶质细胞的激活，有效改善APP/PS1小鼠的学习和记忆。综上所述，我们的研究结果证实，负载BACE1 siRNA的普鲁士蓝纳米复合物具有增强的血脑屏障穿透性和AD协同治疗作用。
