Tailored Reconstituted Lipoprotein for Site-Specific and Mitochondria-Targeted Cyclosporine A Delivery to Treat Traumatic Brain Injury
Tailored Reconstituted Lipoprotein for Site-Specific and Mitochondria-Targeted Cyclosporine A Delivery to Treat Traumatic Brain Injury
复制标题
用于位点特异性和线粒体靶向的环孢素 A 递送的定制重组脂蛋白，用于治疗创伤性脑损伤。
DOI：
10.1021/acsnano.9b09186
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发表时间：
2020-06-23
期刊：
影响因子：
17.1
通讯作者：
Gao, Xiaoling
中科院分区：
文献类型：
--
作者：
Chen, Lepei;Song, Qingxiang;Gao, Xiaoling
创伤性脑损伤（traumatic brain injury，TBI）的继发性损害可导致终身残疾，给患者及其家属带来巨大的经济和心理负担。线粒体作为TBI继发性损伤级联反应的核心介质，是防止细胞死亡和功能障碍扩散的重要靶点。因此，可以在受损部位积累并随后挽救线粒体功能的治疗剂将在很大程度上改善TBI的结果。环孢霉素A（CsA）能够维持线粒体功能的完整性，是治疗TBI最有前途的神经保护剂之一。然而，CsA在TBI中的临床应用在很大程度上受到阻碍，因为它的靶点不佳。为了实现CsA的细胞内靶向递送，我们设计了一种脂蛋白仿生纳米载体，将CsA嵌入核内，并在脂蛋白仿生纳米载体的表面修饰一种基质金属蛋白酶9可激活的细胞穿透肽。在受控皮质撞击损伤小鼠模型中，这种CsA负载的定制重构脂蛋白在受损脑部位有效地积累，进入靶细胞，与线粒体膜结合，更有效地减少神经元损伤，减轻神经炎症，并以1/16的游离CsA剂量挽救记忆缺陷。这些发现提供了强有力的证据，表明TBI中的继发性损伤可以通过靶向CsA递送得到很好的控制，并突出了脂蛋白仿生纳米载体作为TBI管理的灵活纳米平台的潜力。
The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuro-inflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.