Small interfering RNA (siRNA), combining the features of unprecedented potency, target-specificity, and the unique sequence-based disease-intervention model, has received immense considerations over the past decades in the academia and pharmaceutical industry. siRNA fits the criteria of being drug-likely enough to meet with the therapeutic purpose, but its clinical translation has been impeded for a long time by the poor efficiency of in vivo delivery. To reach the cytosol where the RNA interference (RNAi) takes place, siRNA delivery faces a serial of systemic and cellular barriers, especially the endosomal sequestration that would prevent the majority of siRNA from cytosol entry. Transmembrane delivery of siRNA represents a new avenue for efficient delivery by bypassing the endosomal pathway. This rationale is bolstered by the high efficiency of viral entry by membrane fusion, but rarely pursued by artificial siRNA delivery systems. Here, this article provides an opinion of transmembrane delivery by hydrophobic modulation of siRNA. We give a brief introduction of the current siRNA delivery modes, including the hydrophobic cholesterol siRNA conjugates. The cholesterol tagging technology is design on the rationale of hydrophobic siRNAs approach, but hydrophobic modulation throughout the whole siRNA backbone for efficient membrane fusion and transmembrane delivery. The challenge and potential of this technology for preclinical development are also discussed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures.

中文翻译：

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深入了解siRNA跨膜递送-从胆固醇结合到标记。

小干扰RNA（siRNA）结合了空前的效价，靶标特异性和独特的基于序列的疾病干预模型，在过去的几十年中在学术界和制药行业中受到了广泛的考虑。siRNA符合足以达到治疗目的的可能药物的标准，但由于体内递送效率差，其临床翻译长期以来一直受到阻碍。为了到达发生RNA干扰（RNAi）的胞质溶胶，siRNA传递面临一系列系统性和细胞性屏障，尤其是内体隔离，这将阻止大多数siRNA进入胞质。siRNA的跨膜传递代表了绕过内体途径有效传递的新途径。通过膜融合实现病毒进入的高效率支持了这一基本原理，但是人工siRNA传递系统却很少追求这种原理。在这里，本文提供了通过疏水性调节siRNA跨膜递送的观点。我们简要介绍了当前的siRNA传递模式，包括疏水性胆固醇siRNA缀合物。胆固醇标记技术是根据疏水性siRNA方法的原理设计的，但是在整个siRNA主链中进行疏水性调节，以实现有效的膜融合和跨膜递送。还讨论了该技术对临床前开发的挑战和潜力。本文归类于：生物学的纳米技术方法>生物学治疗方法和药物发现中的纳米系统>