A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease.
A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease.
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纳米清洁剂专门穿透病变处的血脑屏障，清除有毒蛋白质并调节阿尔茨海默病的炎症
DOI：
10.1016/j.apsb.2021.04.022
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Lei T;Yang Z;Xia X;Chen Y;Yang X;Xie R;Tong F;Wang X;Gao H
不可逾越的血脑屏障(BBB)和复杂的病理特征是影响阿尔茨海默病(AD)治疗的关键因素。药物在病变部位积聚不良，单纯减少Aβ沉积或TAU蛋白的不良效果亟待解决。在本论文中，我们设计了一种以雷帕霉素ROS响应型PLGA为核心，KLVFF肽和酸可裂解的DAG肽[R@(ox-PLGA)-KCD]修饰的纳米清洁剂。DAG可增强纳米清洗剂对AD皮损中神经血管单位内皮细胞的靶向和内化作用，并随内皮体酸性微环境的改变而脱离，促进纳米清洗剂从内皮细胞向脑实质的转运。然后，暴露的KLVEF可以捕获Aβ并将其携带到小胶质细胞，从而减轻Aβ诱导的神经毒性。值得注意的是，雷帕霉素是一种自噬启动子，在高ROS水平的病变中迅速从纳米清洁剂中释放出来，以改善Aβ的降解并使炎症状态正常化。这种设计总共加速了Aβ的降解，并缓解了氧化应激和过度的炎症反应。总之，我们的发现提供了一种精确定位AD病变的策略，并提供了多管齐下的治疗方法，以清除有毒蛋白和调节病变微环境，从而实现有效的AD治疗。多功能纳米清洁剂[R@(OX-PLGA)-KCD]专为精确的病变输送和多方面协同治疗而设计。通过该系统，成功地减少了AD毒性蛋白的分布，扭转了病变异常的微环境。
Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently. Herein, a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma. Then exposed KLVFF can capture and carry Aβ to microglia, attenuating Aβ-induced neurotoxicity. Strikingly, rapamycin, an autophagy promoter, is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition. This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response. Collectively, our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy. The versatile nanocleaner [R@(ox-PLGA)-KcD] was designed for precise lesion delivery and multi-faceted collaborative treatment. Through this system, the distribution of AD toxic proteins was successfully reduced and the abnormal microenvironment of the lesion was reversed.
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影响因子：
14
作者：
通讯作者：
--
影响因子：
9.3
作者：
Birch AM;Katsouri L;Sastre M
通讯作者：
Sastre M
影响因子：
64.5
作者：
Keren-Shaul, Hadas;Spinrad, Amit;Amit, Ido
通讯作者：
Amit, Ido
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影响因子：
9.1
作者：
Liu, Dingchang;Fu, Dongjie;Sun, Leming
通讯作者：
Sun, Leming
影响因子：
64.8
作者：
Gjoneska E;Pfenning AR;Mathys H;Quon G;Kundaje A;Tsai LH;Kellis M
通讯作者：
Kellis M