Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter
Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter
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DOI：
10.1016/j.biomaterials.2011.10.082
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发表时间：
2012-02-01
期刊：
影响因子：
14
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Yamada, Yuma;Harashima, Hideyoshi
线粒体功能障碍与多种人类疾病有关。现在人们普遍认为，线粒体基因组中的突变和缺陷是这些疾病的基础。因此，线粒体基因治疗和诊断将有望产生巨大的医疗效益。为了实现这样的策略，有必要将治疗剂递送到活细胞中的线粒体中。我们在这里报告了一种通过使用双功能（DF）-MITO-Porter来实现这一目标的方法，该方法针对线粒体基因组，即所谓的线粒体DNA（mtDNA）。DF-MITO-Porter是一种用于线粒体递送的纳米载体，具有通过逐步膜融合穿透内体和线粒体膜的能力。我们首先构建了DF-MITO-Porter包封DNA酶1蛋白作为生物活性货物。当DNA酶I被递送到线粒体时，预期mtDNA将被消化。我们观察了载体的细胞内运输，然后通过DF-MITO-Porter测量了DNase I递送后的线粒体活性和mtDNA水平。这些发现证实了DF-MITO-Porter有效地将DNA酶1递送到线粒体中，并证明了其在选择性治疗线粒体基因组中的潜在用途。(C)2011爱思唯尔有限公司保留所有权利。
Mitochondrial dysfunction has been implicated in a variety of human diseases. It is now well accepted that mutations and defects in the mitochondrial genome form the basis of these diseases. Therefore, mitochondrial gene therapy and diagnosis would be expected to have great medical benefits. To achieve such a strategy, it will be necessary to deliver therapeutic agents into mitochondria in living cells. We report here on an approach to accomplish this via the use of a Dual Function (DF)-MITO-Porter, aimed at the mitochondrial genome, so-called mitochondrial DNA (mtDNA). The DF-MITO-Porter, a nano carrier for mitochondrial delivery, has the ability to penetrate the endosomal and mitochondrial membranes via step-wise membrane fusion. We first constructed a DF-MITO-Porter encapsulating DNase 1 protein as a bioactive cargo. It was expected that mtDNA would be digested, when the DNase I was delivered to the mitochondria. We observed the intracellular trafficking of the carriers, and then measured mitochondrial activity and mtDNA-levels after the delivery of DNase I by the DF-MITO-Porter. The findings confirm that the DF-MITO-Porter effectively delivered the DNase 1 into the mitochondria, and provides a demonstration of its potential use in therapies that are selective for the mitochondrial genome. (C) 2011 Elsevier Ltd. All rights reserved.