Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
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RNA 疗法的内体逃逸：我们如何解决这个限速问题？
DOI：
10.1261/rna.079507.122
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发表时间：
2023-04
期刊：
影响因子：
--
通讯作者：
Dowdy SF
中科院分区：
文献类型：
--
作者：
Dowdy SF
随着超过15种FDA批准的药物上市和大量正在进行的临床试验，RNA治疗剂，如小干扰RNA（siRNA）和反义寡核苷酸（ASO），已经显示出治疗人类疾病的巨大潜力。它们的作用机制完全基于经验证的致病基因的序列，而没有蛋白质结构、活性或细胞位置的先决知识。与被动扩散穿过细胞膜的脂质双层的小分子治疗剂相反，RNA治疗剂太大、太带电和/或太亲水而不能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，内体也由脂质双层屏障组成，其导致内体捕获和保留99%的RNA治疗剂，其中1%或更少进入细胞质。虽然这种非常低水平的内体逃逸已被证明足以治疗肝脏和一些CNS疾病，但对于绝大多数肝外疾病来说是不够的。不幸的是，目前还没有可接受的解决内体逃逸问题的方案。因此，在RNA治疗剂可用于治疗广泛的人类疾病之前，必须以无毒的方式解决内体逃逸的限速递送问题。
With over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis. However, endosomes are also composed of a lipid bilayer barrier that results in endosomal capture and retention of 99% of RNA therapeutics with 1% or less entering the cytoplasm. Although this very low level of endosomal escape has proven sufficient for liver and some CNS disorders, it is insufficient for the vast majority of extra-hepatic diseases. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a nontoxic manner.
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影响因子：
4.6
作者：
Lönn P;Kacsinta AD;Cui XS;Hamil AS;Kaulich M;Gogoi K;Dowdy SF
通讯作者：
Dowdy SF
DOI：
10.1073/pnas.1605731113
发表时间：
2016-09-27
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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Suto M
影响因子：
16
作者：
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通讯作者：
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