Small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) ligands have been used to treat disease in patients. However, conjugates with other ligands deliver siRNA less efficiently, limiting the development of new targeted therapies. Most approaches to enhancing the potency of such conjugates have concentrated on increasing ligand effectiveness and/or the chemical stability of the siRNA drug. One complementary and unexplored alternative is to increase the number of siRNAs delivered per ligand. An ideal system would be a single chemical entity capable of delivering multiple copies of an oligonucleotide drug and/or several such drugs simultaneously. Here we report that siRNAs can be stably linked together under neutral aqueous conditions to form chemically defined siRNA "multimers," and that these multimers can be delivered in vivo by a GalNAc ligand. Conjugates containing multiple copies of the same siRNA showed enhanced activity per unit of ligand, whereas siRNAs targeting different genes linked to a single ligand facilitated multigene silencing in vivo; this is the first demonstration of silencing several genes simultaneously in vivo using ligand-directed multimeric siRNA. Multimeric oligonucleotides represent a powerful and practical new approach to improve intracellular conjugate delivery.

中文翻译：

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配体缀合的多聚siRNA可增强摄取和多重基因沉默。

与N-乙酰半乳糖胺（GalNAc）配体缀合的小干扰RNA（siRNA）已用于治疗患者的疾病。但是，与其他配体的结合物递送siRNA的效率较低，从而限制了新靶向疗法的发展。增强此类缀合物效力的大多数方法都集中在提高siRNA药物的配体有效性和/或化学稳定性上。一种互补且尚未探索的替代方案是增加每个配体递送的siRNA的数量。理想的系统将是能够同时递送多拷贝的寡核苷酸药物和/或几种此类药物的单一化学实体。在这里，我们报道siRNA可以在中性水溶液条件下稳定地连接在一起，从而形成化学定义的siRNA“多聚体”，并且这些多聚体可以通过GalNAc配体体内递送。含有相同siRNA多个拷贝的结合物显示出每单位配体增强的活性，而靶向连接至单个配体的不同基因的siRNA则在体内促进了多基因沉默。这是使用配体定向多聚siRNA在体内同时沉默多个基因的第一个证明。多聚体寡核苷酸代表了一种强大而实用的新方法，可以改善细胞内结合物的递送。这是使用配体定向多聚siRNA在体内同时沉默多个基因的第一个证明。多聚体寡核苷酸代表了一种强大而实用的新方法，可以改善细胞内结合物的递送。这是使用配体定向多聚siRNA在体内同时沉默多个基因的第一个证明。多聚体寡核苷酸代表了一种强大而实用的新方法，可以改善细胞内结合物的递送。