Liver-targeted Nano-MitoPBN normalizes glucose metabolism by improving mitochondrial redox balance
Liver-targeted Nano-MitoPBN normalizes glucose metabolism by improving mitochondrial redox balance
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肝脏靶向 Nano-MitoPBN 通过改善线粒体氧化还原平衡使葡萄糖代谢正常化
DOI：
10.1016/j.biomaterials.2019.119457
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发表时间：
2019
期刊：
影响因子：
14
通讯作者：
Shi Dongyun
中科院分区：
文献类型：
--
作者：
Wu Meiling;Liao Lihao;Jiang Lihan;Zhang Chunwang;Gao Hongyang;Qiao Liang;Liu Shanlin;Shi Dongyun
纳米医学的最新进展通过提高药物输送效率提供了有希望的疾病治疗，但临床应用遇到了困难，很大程度上是由于大多数注射的纳米颗粒被隔离在肝脏中。相比之下，肝细胞似乎是纳米粒子的完美靶标。在这里，我们产生了一种新的脂质体封装 Nano-MitoPBN 配方，作为肝脏线粒体靶向自由基清除剂。我们发现Nano-MitoPBN主要积聚在肝细胞中，并清除电子传递链（ETC）复合物I和III的单电子泄漏产生的肝线粒体超氧化物/过氧化氢。由于微区室化，Nano-MitoPBN 增加了线粒体 3 态呼吸频率和呼吸控制比（RCR），导致 NADH:NAD+ 比率降低，改善线粒体氧化能量耦合和 ATP 合成，从而减轻 ROS 诱导的线粒体功能障碍。功能性线粒体促进肝脏对底物的氧化，导致糖酵解和TCA循环增加，直接加速葡萄糖分解，从而降低外周血糖水平，改善糖尿病动物的糖耐量受损。我们的研究表明肝线粒体靶向抗氧化纳米药物治疗糖尿病的潜力。
Recent advances in Nanomedicine provide promising disease treatment through improved drug delivery efficiency, but clinical applications have encountered difficulties, largely due to the majority of injected nanoparticle is sequestered in liver. In contrast, liver cells seem to be a perfect target for nanoparticles. Here we generated a new formula of liposome encapsulated Nano-MitoPBN as a liver mitochondrial-targeting free radical scavenger. We found that Nano-MitoPBN mainly accumulated in hepatocytes and scavenged hepatic mitochondrial superoxide/hydrogen peroxide generated from mono-electron leak of electron transport chain (ETC) complex I and III. Due to micro-compartmentalization, Nano-MitoPBN increased mitochondrial state 3 respiratory rate and respiratory control ratio (RCR), resulting in decreased NADH:NAD+ratio, improved mitochondrial oxidative energy coupling and ATP synthesis, thus alleviating ROS-induced mitochondrial dysfunction. The functional mitochondria promoted the substrate oxidation by the liver, resulting in increased glycolysis and TCA cycle, which directly speeds glucose decomposition, thus decreasing the peripheral blood glucose level and improving the impaired glucose tolerance in diabetic animals. Our study suggests the potential of liver mitochondrial targeting antioxidative nanomedicines for diabetes mellitus.