Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factor in sporadic Alzheimer's disease (AD). Neuronal mitochondria have been proposed to be a promising therapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloid-β (Aβ) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological environment. Recently, biomaterials-based nanomedicine has been widely investigated for the treatment of AD. Herein, we devised a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules attached to the RBC membrane surface (RVG/TPP NPs@RBCm). With the advantage of suitable physicochemical properties of NLC and unique biological functions of the RBC membrane, RVG/TPP NPs@RBCm are stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of RVG29 and TPP, RVG/TPP NPs@RBCm can not only penetrate the blood-brain barrier (BBB) but also target neuron cells and further localize in the mitochondria. After encapsulating Resveratrol (RSV) as the model antioxidant, the data demonstrated that RVG/TPP-RSV NPs@RBCm can relieve AD symptoms by mitigating Aβ-related mitochondrial oxidative stress both in vitro and in vivo. The memory impairment in APP/PS1 mice is significantly improved following the systemic administration of RVG/TPP-RSV NPs@RBCm. In conclusion, intravenous neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems are a promising therapeutic candidate for ROS-induced mitochondrial dysfunction in AD.

中文翻译：

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神经元线粒体靶向治疗阿尔茨海默氏病，通过使用双重修饰的新型仿生纳米系统全身性输送白藜芦醇。

活性氧（ROS）诱导的神经元线粒体功能障碍是偶发性阿尔茨海默病（AD）的关键病理因素。已经提出神经元线粒体是AD的有希望的治疗靶标，特别是对于常规淀粉样β（Aβ）靶向治疗的III期临床试验的失败。然而，由于复杂的生理环境，将治疗剂有效地静脉内递送至脑中神经元线粒体仍然是主要挑战。近来，基于生物材料的纳米药物已被广泛研究用于AD的治疗。在这里 我们设计了一种将抗氧化剂装载到红细胞（RBC）膜包裹的纳米结构脂质载体（NLC）中的功能性抗氧化剂，该功能性抗氧化剂可以传递到神经元线粒体，该脂质载体带有狂犬病病毒糖蛋白（RVG29）和附着在RBC膜表面的三苯基膦阳离子（TPP）分子（RVG / TPP NPs @ RBCm）。凭借NLC合适的理化特性和RBC膜独特的生物学功能，RVG / TPP NPs @ RBCm得以稳定并能够持续释放药物，从而改善了生物相容性和长期循环。在RVG29和TPP的协同作用下，RVG / TPP NPs @ RBCm不仅可以穿透血脑屏障（BBB），而且可以靶向神经元细胞并进一步定位于线粒体。将白藜芦醇（RSV）封装为模型抗氧化剂后，数据表明，RVG / TPP-RSV NPs @ RBCm可以通过减轻体内和体外Aβ相关的线粒体氧化应激来缓解AD症状。全身性施用RVG / TPP-RSV NPs @ RBCm后，APP / PS1小鼠的记忆障碍得到了明显改善。总之，静脉内靶向神经元线粒体的双重修饰新型仿生纳米系统是ROS引起的AD线粒体功能障碍的有前途的治疗候选药物。