RNA therapeutics, including siRNAs, antisense oligonucleotides, and other oligonucleotides, have great potential to selectively treat a multitude of human diseases, from cancer to COVID to Parkinson's disease. RNA therapeutic activity is mechanistically driven by Watson–Crick base pairing to the target gene RNA without the requirement of prior knowledge of the protein structure, function, or cellular location. However, before widespread use of RNA therapeutics becomes a reality, we must overcome a billion years of evolutionary defenses designed to keep invading RNAs from entering cells. Unlike small-molecule therapeutics that are designed to passively diffuse across the cell membrane, macromolecular RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and are instead taken up into cells by endocytosis. However, similar to the cell membrane, endosomes comprise a lipid bilayer that entraps 99% or more of RNA therapeutics, even in semipermissive tissues such as the liver, central nervous system, and muscle. Consequently, before RNA therapeutics can achieve their ultimate clinical potential to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a clinically acceptable manner.

中文翻译：

---

RNA 治疗的传递：伟大的内体逃逸！

RNA 疗法，包括 siRNA、反义寡核苷酸和其他寡核苷酸，具有选择性治疗多种人类疾病的巨大潜力，从癌症到新冠肺炎再到帕金森病。RNA 治疗活性是由与靶基因 RNA 的 Watson-Crick 碱基配对驱动的，无需事先了解蛋白质结构、功能或细胞位置。然而，在RNA疗法的广泛使用成为现实之前，我们必须克服十亿年来旨在阻止入侵RNA进入细胞的进化防御。与设计用于被动扩散穿过细胞膜的小分子治疗剂不同，大分子 RNA 治疗剂太大、带电太多和/或太亲水，无法被动扩散穿过细胞膜，而是通过内吞作用被吸收到细胞中。然而，与细胞膜类似，内体包含脂质双层，即使在肝脏、中枢神经系统和肌肉等半允许组织中，也能捕获 99% 或更多的 RNA 治疗剂。因此，在RNA疗法能够实现治疗广泛的人类疾病的最终临床潜力之前，必须以临床可接受的方式解决内体逃逸的限速递送问题。