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首页> 外文期刊>Biochemistry >Insight into the Cellular Uptake Mechanism of a Secondary Amphipathic Cell-Penetrating Peptide for siRNA Delivery
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Insight into the Cellular Uptake Mechanism of a Secondary Amphipathic Cell-Penetrating Peptide for siRNA Delivery

机译：洞察到用于siRNA传递的二级两亲性细胞穿透肽的细胞摄取机制。

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摘要

Delivery of siRNA remains a major limitation to their clinical application, and several technologiesnhave been proposed to improve their cellular uptake.We recently described a peptide-based nanoparticle systemnfor efficient delivery of siRNA into primary cell lines: CADY. CADY is a secondary amphipathic peptide thatnforms stable complexes with siRNA and improves their cellular uptake independently of the endosomalnpathway. In the present work, we have combinedmolecularmodeling, spectroscopy, andmembrane interactionnapproaches in order to gain further insight into CADY/siRNA particle mechanism of interaction withnbiological membrane. We demonstrate that CADY forms stable complexes with siRNA and binds phospho-nlipids tightly, mainly through electrostatic interactions. Binding to siRNA or phospholipids triggers anconformational transition of CADY from an unfolded state to an R-helical structure, thereby stabilizingnCADY/siRNA complexes and improving their interactions with cell membranes. Therefore, we propose thatnCADY cellular membrane interaction is driven by its structural polymorphism which enables stabilization ofnboth electrostatic and hydrophobic contacts with surface membrane proteoglycan and phospholipids.
机译：siRNA的传递仍然是其临床应用的主要限制，并且已经提出了几种改善其细胞摄取的技术。我们最近描述了一种基于肽的纳米颗粒系统，用于将siRNA有效地传递到原代细胞系：CADY。 CADY是一种二级两亲性肽，可与siRNA形成稳定的复合物，并独立于内吞途径而改善其细胞摄取。在目前的工作中，我们结合了分子建模，光谱学和膜相互作用的方法，以进一步了解CADY / siRNA颗粒与生物膜相互作用的机理。我们证明，CADY与siRNA形成稳定的复合物，并主要通过静电相互作用紧密结合磷脂。与siRNA或磷脂结合会触发CADY从未折叠状态到R螺旋结构的构象转变，从而稳定nCADY / siRNA复合物并改善其与细胞膜的相互作用。因此，我们提出nCADY细胞膜相互作用是由其结构多态性驱动的，该结构多态性使得与表面膜蛋白聚糖和磷脂的静电和疏水接触均得以稳定。

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