文献：Neuronal mitochondria-targeted therapy for Alzheimer’s disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems

文献链接：https://pubmed.ncbi.nlm.nih.gov/32228100/

作者：Yang Han, Xiaoyang Chu, Lin Cui, Shiyao Fu, Chunsheng Gao, Yi Li & Baoshan Sun

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氨基-rvg29和羧基-tpp

原文摘要：Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factorin sporadic Alzheimer’s disease (AD). Neuronal mitochondria have been proposed to be a promisingtherapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloidb (Ab) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronalmitochondria 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/TPPRSV NPs@RBCm can relieve AD symptoms by mitigating Ab-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.

近年来，基于生物材料的纳米药物在AD中得到了研究。在此，设计了一种功能性抗氧化剂传递到红细胞（RBC）的策略，将红细胞（RBC）膜包覆纳米结构脂质载体（NLC），携带RVG29和TPP附着在红细胞膜表面的TPP分子（RVG/TPP NPs@RBCm）。RVG/TPP NPs@RBCm具有合适的NLC理化性质和RBC膜生物学功能，能够稳定使药物持续释放，改善生物相容性和长期循环。

图为：新型仿生纳米系统的初步安全性评价

新型仿生纳米系统的制备:

准备普通NPs@RBCm， RSV加载NPs或疏水探针标记与红细胞膜囊泡，然后挤压通过纳米聚碳酸酯膜获得RSV NPs@RBCm或疏水探针标记NPs@RBCm。此外，通过插入后的方法形成了RVG29修饰的NPs@RBCm（RVG NPs@RBCm）、TPP修饰的NPs@RBCm（TPPNPs@RBCm）和同时修饰RVG29和TPP的NPs（RVG/TPPNPs@RBCm）。简单地说，通过旋转蒸发法制备了DSPE-PEG2000-RVG29或DSPE-PEG2000-TPP的脂质膜，并在真空下进一步干燥。干燥的脂质膜随后补水与PBS形成胶束。RVG NPs@RBCm或TPP NPs@RBCm准备，胶束解决方案DSPE-PEG2000- RVG29或DSPE-PEG2000-TPP加入预制NPs@RBCm和孵化。对于RVG/TPP NPs@RBCm的制备，根据筛选结果，使用上述条件，将一定数量的DSPE-PEG2000-RVG和DSPE-PEG2000-TPP与预制的NPs@RBCm孵育。

图为：RVG/TPP-RSV NPs@RBCm的理化表征。

结论：DSPE-PEG2000-RVG29/DSPEPEG2000-TPP作为一种两亲性分子，在温和的条件下可以很容易地插入RBC膜的外单层，形成RVG/TPP NPs@RBCm。RVG/TPP NPs@RBCm的透射电镜图像显示，其粒径与激光粒子分析仪测量的粒径非常接近。配体修饰的新型仿生纳米体系的zeta电位高于NPs@RBCm。