In vivo delivery of transcription factors with multifunctional oligonucleotides.
In vivo delivery of transcription factors with multifunctional oligonucleotides.
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DOI：
10.1038/nmat4269
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发表时间：
2015-07
期刊：
影响因子：
41.2
通讯作者：
Murthy N
中科院分区：
文献类型：
--
作者：
Lee K;Rafi M;Wang X;Aran K;Feng X;Lo Sterzo C;Tang R;Lingampalli N;Kim HJ;Murthy N
基于转录因子的治疗有可能彻底改变医学，但由于递送问题，临床成功有限。转录因子的递送是具有挑战性的，因为它需要开发能够以最小的毒性复合转录因子、靶向细胞并刺激内体破坏的递送载体。在这份报告中，我们提出了一种新的多功能寡核苷酸，称为DARTs（DNA组装重组转录因子），它可以在体内高效率地传递转录因子。DARTs由含有转录因子结合序列的寡核苷酸和被酸可裂解半乳糖残基掩蔽的疏水膜破坏性链组成。DARTs具有独特的分子结构，这允许它们结合转录因子，触发肝细胞中的内吞作用，并刺激内体破坏。由于半乳糖残基，DART靶向肝细胞，并且可以以最小的毒性有效地破坏内体，因为在内体的酸性环境中选择性地发生其疏水结构域的解蔽。我们在这里表明，DARTs可以将转录因子核红细胞2相关因子2（Nrf2）传递到肝脏，催化Nrf2下游基因的转录，并将小鼠从对乙酰氨基酚诱导的肝损伤中拯救出来。
Therapeutics based on transcription factors have the potential to revolutionize medicine but have had limited clinical success due to delivery problems. The delivery of transcription factors is challenging because it requires developing a delivery vehicle that can complex transcription factors, target cells, and stimulate endosomal disruption, with minimal toxicity. In this report we present a novel multifunctional oligonucleotide, termed DARTs (DNA Assembled Recombinant Transcription factors), which can deliver transcription factors with high efficiency in vivo. DARTs are composed of an oligonucleotide that contains a transcription factor binding sequence and hydrophobic membrane disruptive chains that are masked by acid cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to bind transcription factors, trigger endocytosis in hepatocytes, and stimulate endosomal disruption. The DARTs target hepatocytes as a result of the galactose residues and can disrupt endosomes efficiently with minimal toxicity, because unmasking of their hydrophobic domains selectively occurs in the acidic environment of the endosome. We show here that DARTs can deliver the transcription factor Nuclear erythroid 2-related factor 2 (Nrf2) to the liver, catalyze the transcription of Nrf2 downstream genes, and rescue mice from acetaminophen induced liver injury.