Artificial Nucleobase-Directed Programmable Synthesis and Assembly of Amphiphilic Nucleic Acids as an All-in-One Platform for Cation-Free siRNA Delivery.
Artificial Nucleobase-Directed Programmable Synthesis and Assembly of Amphiphilic Nucleic Acids as an All-in-One Platform for Cation-Free siRNA Delivery.
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DOI：
10.1021/acsami.2c09406
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发表时间：
2022-09
影响因子：
9.5
通讯作者：
Can Luo;Yuqi Xie;Minze He;Yin-Zheng Xia;Yazhou Li;Lei He;Jili Li;Linlin Wang;Xiaoyan Han;Lili Zhang;Xi Yuan;Zhiqiang Wang;Yanlan Liu;Weihong Tan
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文献类型：
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作者：
Can Luo;Yuqi Xie;Minze He;Yin-Zheng Xia;Yazhou Li;Lei He;Jili Li;Linlin Wang;Xiaoyan Han;Lili Zhang;Xi Yuan;Zhiqiang Wang;Yanlan Liu;Weihong Tan
将核酸治疗剂有效转运到靶细胞中是疾病治疗中遗传调节的关键步骤。如今，递送系统强烈依赖于阳离子材料，但如何平衡这些外源性材料的有效性和毒性之间的权衡仍然具有极大的挑战性。在这里，我们从核酸化学中获得灵感，并引入了一个新的概念，两亲性核酸（ANA），作为一个多合一的平台，用于无阳离子核酸递送，通过编程缀合两个不同的人工核碱基与序列无关的活动。具体地，ANA中的亲水性人工核碱基充当递送载体和治疗货物以获得综合益处，而疏水性核碱基使得能够进行分子自组装以改善稳定性和进行内体膜氧化以增强内体逃逸。凭借这些优点，该平台成功地用于短干扰RNA（siRNA）递送，其表现出高siRNA负载能力、快速细胞摄取和有效的内体逃逸，引发显著的基因沉默和对癌细胞增殖和迁移的协同抑制作用。这项工作是利用核酸化学基础为晚期癌症治疗诊断学提供新范式的案例研究。
Efficient transport of nucleic acid therapeutics into targeted cells is the key step of genetic modulation in disease treatment. Nowadays, delivery systems strongly rely on cationic materials, but how to balance the trade-off between effectiveness and toxicity of these exogenous materials remains incredibly challenging. Here, we take inspiration from nucleic acid chemistry and introduce a new concept of amphiphilic nucleic acids (ANAs), as an all-in-one platform for cation-free nucleic acid delivery, by programmatically conjugating two different artifical nucleobases with sequence-independent activities. Specifically, the hydrophilic artificial nucleobases in ANAs act as both delivery vectors and therapeutic cargos for integrated benefits, while the hydrophobic nucleobases enable molecular self-assembly for improved stability and endosomal membrane oxidation for enhanced endosomal escape. By virtue of these merits, this platform is successfully used for short interference RNA (siRNA) delivery, which demonstrates a high siRNA loading capacity, rapid cellular uptake, and efficient endosomal escape, eliciting remarkable gene silencing and synergistic inhibitory effects on cancer cell proliferation and migration. This work is a case study in exploiting the basis of nucleic acid chemistry to afford new paradigms for advanced cancer theranostics.