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Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes
Nature Nanotechnology ( IF 38.1 ) Pub Date : 2024-09-19 , DOI: 10.1038/s41565-024-01785-0
Yan Zhuo , Zhen Luo , Zhu Zhu , Jie Wang , Xiang Li , Zhuan Zhang , Cong Guo , Bingqi Wang , Di Nie , Yong Gan , Guoqing Hu , Miaorong Yu

Efficient cytosolic delivery is a significant hurdle when using short interfering RNA (siRNA) in therapeutic applications. Here we show that cholesterol-rich exosomes are prone to entering cancer cells through membrane fusion, achieving direct cytosolic delivery of siRNA. Molecular dynamics simulations suggest that deformation and increased contact with the target cell membrane facilitate membrane fusion. In vitro we show that cholesterol-enriched milk-derived exosomes (MEs) achieve a significantly higher gene silencing effect of siRNA, inducing superior cancer cell apoptosis compared with the native and cholesterol-depleted MEs, as well as conventional transfection agents. When administered orally or intravenously to mice bearing orthotopic or subcutaneous tumours, the cholesterol-enriched MEs/siRNA exhibit antitumour activity superior to that of lipid nanoparticles. Collectively, by modulating the cholesterol content of exosome membranes to facilitate cell entry via membrane fusion, we provide a promising approach for siRNA-based gene therapy, paving the way for effective, safe and simple gene therapy strategies.



中文翻译:


使用富含胆固醇的外泌体通过细胞膜融合直接胞质递送 siRNA



在治疗应用中使用短干扰 RNA (siRNA) 时,有效的胞质递送是一个重大障碍。在这里,我们发现富含胆固醇的外泌体很容易通过膜融合进入癌细胞,实现siRNA的直接胞质递送。分子动力学模拟表明,变形和增加与靶细胞膜的接触有利于膜融合。在体外,我们发现富含胆固醇的牛奶来源的外​​泌体 (ME) 实现了显着更高的 siRNA 基因沉默效果,与天然和去除胆固醇的 ME 以及传统转染剂相比,可诱导更优异的癌细胞凋亡。当对患有原位或皮下肿瘤的小鼠口服或静脉注射时,富含胆固醇的ME/siRNA表现出优于脂质纳米颗粒的抗肿瘤活性。总的来说,通过调节外泌体膜的胆固醇含量以促进膜融合进入细胞,我们为基于 siRNA 的基因治疗提供了一种有前景的方法,为有效、安全和简单的基因治疗策略铺平了道路。

更新日期:2024-09-19
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