蜂毒素衍生肽介导的纳米颗粒 siRNA 转染的机制。
Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides.
机构信息
Computational and Molecular Biophysics, Washington University School of Medicine , St. Louis, Missouri. 63108, United States.
出版信息
ACS Nano. 2013 Oct 22;7(10):8605-15. doi: 10.1021/nn403311c. Epub 2013 Sep 26.
Abstract
Traditional peptide-mediated siRNA transfection via peptide transduction domains exhibits limited cytoplasmic delivery of siRNA due to endosomal entrapment. This work overcomes these limitations with the use of membrane-destabilizing peptides derived from melittin for the knockdown of NFkB signaling in a model of adult T-cell leukemia/lymphoma. While the mechanism of siRNA delivery into the cytoplasmic compartment by peptide transduction domains has not been well studied, our analysis of melittin derivatives indicates that concurrent nanocomplex disassembly and peptide-mediated endosomolysis are crucial to siRNA transfection. Importantly, in the case of the most active derivative, p5RHH, this process is initiated by acidic pH, indicating that endosomal acidification after macropinocytosis can trigger siRNA release into the cytoplasm. These data provide general principles regarding nanocomplex response to endocytosis, which may guide the development of peptide/siRNA nanocomplex-based transfection.
摘要
传统的通过肽转导结构域介导的小干扰 RNA（siRNA）转染由于被内体捕获，导致 siRNA 在细胞质中的递送受到限制。本研究使用来源于蜂毒素的破坏膜的肽克服了这些限制，用于在成人 T 细胞白血病/淋巴瘤模型中敲低 NFkB 信号。虽然肽转导结构域将 siRNA 递送到细胞质区室的机制尚未得到很好的研究，但我们对蜂毒素衍生物的分析表明，同时进行纳米复合物解组装和肽介导的内体溶酶体分解对于 siRNA 的转染至关重要。重要的是，在最活跃的衍生物 p5RHH 的情况下，该过程由酸性 pH 引发，表明巨胞饮作用后的内体酸化可以触发 siRNA 释放到细胞质中。这些数据提供了关于纳米复合物对内吞作用的反应的一般原则，这可能指导基于肽/siRNA 纳米复合物的转染的发展。
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