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Design and enhanced gene silencing activity of spherical 2′-fluoroarabinose nucleic acids (FANA-SNAs)
Chemical Science ( IF 8.4 ) Pub Date : 2021-1-15 , DOI: 10.1039/d0sc06645a
Hassan H Fakih 1 , Adam Katolik 1 , Elise Malek-Adamian 1 , Johans J Fakhoury 1 , Sepideh Kaviani 1 , Masad J Damha 1 , Hanadi F Sleiman 1
Affiliation  

Drug delivery vectors for nucleic acid therapeutics (NATs) face significant barriers for translation into the clinic. Spherical nucleic acids (SNAs) – nanoparticles with an exterior shell made up of DNA strands and a hydrophobic interior – have recently shown great potential as vehicles to improve the biodistribution and efficacy of NATs. To date, SNA design has not taken advantage of the powerful chemical modifications available to NATs. Here, we modify SNAs with 2′-deoxy-2′-fluoro-D-arabinonucleic acid (FANA-SNA), and show increased stability, enhanced gene silencing potency and unaided uptake (gymnosis) as compared to free FANA. By varying the spacer region between the nucleic acid strand and the attached hydrophobic polymer, we show that a cleavable DNA based spacer is essential for maximum activity. This design feature will be important when implementing functionalized nucleic acids into nanostructures for gene silencing. The modularity of the FANA-SNA was demonstrated by silencing two different targets. Transfection-free delivery was superior for the modified SNA compared to the free FANA oligonucleotide.

中文翻译:

球形2'-氟阿拉伯糖核酸(FANA-SNAs)的设计和增强的基因沉默活性

核酸治疗药物(NATs)的药物输送载体面临着转化为临床的重大障碍。球形核酸(SNA)是一种具有由DNA链组成的外壳和疏水内部的纳米颗粒,最近已显示出巨大的潜力,可作为改善NAT的生物分布和功效的媒介。迄今为止,SNA设计还没有利用可用于NAT的强大化学修改方法。在这里,我们用2'-deoxy-2'-fluoro- D修饰SNA-阿拉伯核糖核酸(FANA-SNA),与游离FANA相比,具有更高的稳定性,增强的基因沉默潜能和独立的摄取(妇科病)。通过改变核酸链与连接的疏水性聚合物之间的间隔区,我们显示出基于可切割DNA的间隔区对于最大活性至关重要。当将功能化的核酸实施到纳米结构以实现基因沉默时,此设计功能将非常重要。FANA-SNA的模块化通过沉默两个不同的目标得到了证明。与游离的FANA寡核苷酸相比,修饰的SNA的无转染递送效果更好。
更新日期:2021-01-15
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