Allen Randall, Yokota Toshifumi
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Sciences Research, Edmonton, AB T6G 2H7, Canada.
Molecules. 2024 Dec 19;29(24):5997. doi: 10.3390/molecules29245997.
Therapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological agents, including the ability to target previously "undruggable" genes. Despite this promise, several biological barriers severely limit their clinical efficacy. Upon administration, TNAs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1-2% of TNAs successfully escape endosomal compartments to reach the cytosol, and in some cases the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of TNAs. This review explores the current understanding of TNA endosomal escape and nuclear transport along with strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-TNA conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in TNA-based therapeutics can be realized, ultimately expanding their clinical utility.
治疗性核酸（TNAs），包括反义寡核苷酸（ASOs）和小干扰RNA（siRNA），已成为多种疾病颇具前景的治疗策略，具有以高度特异性调节基因表达的潜力。这些小的合成核酸样分子相对于传统药物具有独特优势，包括能够靶向先前“不可成药”的基因。尽管有此前景，但一些生物学屏障严重限制了它们的临床疗效。给药后，TNAs主要通过内吞作用进入细胞，被困在称为内体的膜结合囊泡内。研究估计，只有1-2%的TNAs成功逃离内体区室到达细胞质，在某些情况下到达细胞核，在那里它们结合靶mRNA并发挥治疗作用。因此，内体截留和低效的核定位是TNAs治疗应用中的关键瓶颈。本综述探讨了目前对TNA内体逃逸和核转运的理解以及旨在克服这些挑战的策略，包括使用内体逃逸剂、肽-TNA缀合物、非病毒递送载体和核定位信号。通过改善内体逃逸和核定位，可以在基于TNA的治疗方面取得重大进展，最终扩大其临床应用。
