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Green nanoparticles for oligonucleotide delivery

Gene Therapy volume 27, pages 535–536 (2020)Cite this article

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Oligonucleotide is a short, versatile polynucleotide DNA or RNA chain that usually consists of 8–50 nucleotides. It could be an anti-sense oligonucleotide (ASO), a complementary chain of target mRNA, blocking the transcription process to proteins. It could act as an aptamer with strong affinity towards certain molecules. Besides, oligonucleotide could also be other functional molecules such as splice-switching oligonucleotide, anti-gene oligonucleotide, small interference RNA (siRNA), ribozymes, etc. Oligonucleotide possesses a general structure composed of ribose/deoxyribose, five types of bases (AGTCU) and phosphoric acid and thus it can be readily prepared by organic synthesis. In addition, oligonucleotides are believed to demonstrate higher specificity, lower side effect, less cytotoxicity and lower possibility to cause drug resistance than small molecule drugs. For these reasons, gene therapy using oligonucleotides has aroused great interest and tremendous efforts have been devoted to the use of oligonucleotide therapies for the treatment of various diseases in the past decades.

In 1978, Zamecnik and Stephenson firstly demonstrated a synthetic ASO with 13 nucleotides that can effectively inhibit the virus replication [1]. Later since Vitravene (Fomivirsen), an ASO, was firstly approved by FDA in 1998 for the treatment of patients with peripheral cytomegalovirus (CMV) retinitis complicated with AIDS [2], during the past 20 years, several oligonucleotide therapies have then been subsequently approved for the treatment of other diseases [3]. However, some technical challenges still need to be addressed to accelerate the development of oligonucleotide therapies. The first issue is related to the fragility and instability of the oligonucleotide, especially the single-strand oligonucleotide, which can be easily degraded by intracellular nuclease [4]. And it is noted that approximately half of the oligonucleotide drugs approved by FDA nowadays are single-strand oligonucleotides. The second issue is that oligonucleotides need to be precisely delivered to the target tissue and the right intracellular compartment before it could take effect [5], but naked or unmodified oligonucleotides are usually negatively charged and are poorly internalized by cells [6]. At last, oligonucleotide therapies usually have dose requirement, and dose below the threshold would result in inefficient therapies [7].

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Funding

This work was supported by the Beijing Natural Science Foundation (JQ18006).

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  1. Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, 100084, Beijing, China

    Yuanyu Zhang & Jun Ge

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  1. Yuanyu Zhang
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Correspondence to Jun Ge.

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Zhang, Y., Ge, J. Green nanoparticles for oligonucleotide delivery. Gene Ther 27, 535–536 (2020). https://doi.org/10.1038/s41434-020-0173-5

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