Short interfering RNA (siRNA) has broad applications in biology and medicine, and holds tremendous potential to become a new class of therapeutics for many diseases. As a highly anionic macrobiomolecule, its cytosolic delivery, however, has been a major roadblock in translation. Here, we report the development of small, bifunctional chemical tags capable of transporting siRNA directly into the cytosol. The bifunctional tags consist of a siRNA-binding moiety that interacts with siRNA non-covalently, and a steroid domain that readily fuses with the mammalian cell membrane. In contrast to the conventional covalently conjugated siRNA-steroid that enters cells largely via endocytosis which substantially limits siRNA bioavailability, the non-covalently tagged siRNA is cell membrane-permeant, avoiding the endocytic pathway. This new methodology enables effective RNA interference (RNAi) without the need of cationic transfection or endosomolytic agents, opening a new avenue for intracellular delivery of native biologics.

短干扰RNA（siRNA）在生物学和医学领域具有广泛的应用，并具有成为许多疾病的新型治疗方法的巨大潜力。作为一种高度阴离子化的大分子，其胞质传递一直是翻译的主要障碍。在这里，我们报告了能够将siRNA直接转运到细胞质中的小型双功能化学标签的发展。双功能标签由与siRNA非共价相互作用的siRNA结合部分和易于与哺乳动物细胞膜融合的类固醇结构域组成。与传统的共价结合的siRNA-类固醇主要通过细胞进入细胞内吞作用极大地限制了siRNA的生物利用度，非共价标记的siRNA可透过细胞膜，从而避免了内吞途径。这种新方法无需阳离子转染或内溶菌剂即可实现有效的RNA干扰（RNAi），从而为天然生物制剂的细胞内递送开辟了一条新途径。