RNA interference (RNAi) applications have evolved from experimental tools to study gene function to the development of a novel class of gene-silencing therapeutics. Despite decades of research, it was not until August 2018 that the US FDA approved the first-ever RNAi drug, marking a new era for RNAi therapeutics. Although there are many limitations associated with the inherent structure of RNA, delivery to target cells and tissues remains the most challenging. RNAs are unable to diffuse across cellular membranes due to their large size and polyanionic backbone and, therefore, require a delivery vector. RNAi molecules can be conjugated to a targeting ligand or packaged into a delivery vehicle. Alnylam has used both strategies in their FDA-approved formulations to achieve efficient delivery to the liver. To harness the full potential of RNAi therapeutics, however, we must be able to target additional cells and tissues. One promising target is the folate receptor α, which is overexpressed in a variety of tumors despite having limited expression and distribution in normal tissues. Folate can be conjugated directly to the RNAi molecule or used to functionalize delivery vehicles. In this review, we compare both delivery strategies and discuss the current state of research in the area of folate-mediated delivery of RNAi molecules.

中文翻译：

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共轭还是封装？看看通过叶酸受体靶向 siRNA 传递

RNA 干扰 (RNAi) 应用已经从研究基因功能的实验工具发展到开发一类新型基因沉默疗法。尽管进行了数十年的研究，但直到 2018 年 8 月，美国 FDA 才批准了第一个 RNAi 药物，标志着 RNAi 疗法的新时代。尽管存在许多与 RNA 的固有结构相关的限制，但向靶细胞和组织的递送仍然是最具挑战性的。由于其大尺寸和聚阴离子骨架，RNA 无法扩散穿过细胞膜，因此需要递送载体。RNAi 分子可以与靶向配体结合或包装到递送载体中。Alnylam 在其 FDA 批准的配方中使用了这两种策略，以实现对肝脏的有效递送。然而，为了充分利用 RNAi 疗法的潜力，我们必须能够靶向额外的细胞和组织。一个有希望的靶点是叶酸受体 α，尽管它在正常组织中的表达和分布有限，但它在各种肿瘤中过表达。叶酸可直接与 RNAi 分子结合或用于功能化递送载体。在这篇综述中，我们比较了两种递送策略，并讨论了叶酸介导的 RNAi 分子递送领域的研究现状。叶酸可直接与 RNAi 分子结合或用于功能化递送载体。在这篇综述中，我们比较了两种递送策略，并讨论了叶酸介导的 RNAi 分子递送领域的研究现状。叶酸可直接与 RNAi 分子结合或用于功能化递送载体。在这篇综述中，我们比较了两种递送策略，并讨论了叶酸介导的 RNAi 分子递送领域的研究现状。