The development and improvement of ribonucleic acid therapy strategies

Abstract

The biological understanding of RNA has evolved since the discovery of catalytic RNAs in the early 1980s and the establishment of RNA interference (RNAi) in the 1990s. RNA is no longer seen as the simple mid-product between transcription and translation, but potential molecules to be developed as RNA therapeutic drugs. RNA-based therapeutic drugs have gained recognition due to their ability to regulate gene expression and perform cellular functions. Various nucleobase, backbone, and sugar-modified oligonucleotides have been synthesized, as natural oligonucleotides with some limitations such as poor low nuclease resistance, binding affinity, poor cellular uptake and toxicity, which affect their use as RNA therapeutic drugs. In this review, we briefly discuss different RNA therapeutic drugs and the internal connection, including antisense oligonucleotides, siRNA and miRNA, aptamers, saRNA, and RNA vaccines, we also discuss the important roles of RNA vaccines and their use in the fight against COVID-19. In addition, various chemical modifications and delivery systems used to improve the performance of RNA therapeutic drugs and overcome their limitations are discussed.

Improving Stability and Specificity of CRISPR/Cas9 System by Selective Modification of Guide RNAs with 2′-fluoro and Locked Nucleic Acid Nucleotides

“…The particular type and pattern of chemical modifications can be selected on the basis of data regarding the structure of the guide RNAs/Cas9 protein complex, interactions of guide RNAs with the Cas9 protein [ 28 , 35 , 36 ] and experimental results on modified guide RNA properties in CRISPR/Cas9 systems [ 9 , 14 , 15 , 16 , 17 , 18 , 19 , 34 ]. The lessons learned from early proposed RNA-based gene expression regulation technologies [ 37 , 38 , 39 ] can also be taken into account upon the design of modified guide RNAs.…”

Development and application of ribonucleic acid therapy strategies against COVID-19

“…Under most circumstances, RNA therapies can be classified into several categories, including antisense oligonucleotides (ASO) which inhibit the translation of mRNA, RNAi, aptamers that could bind proteins and other molecular ligands, small activating RNAs (saRNAs) with the ability to activate genes, catalytic RNAs or called ribozymes, RNA vaccines and gene editing approaches such as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas (CRISPR-associated) systems 20 . RNA based biotherapeutics have natural advantages over the traditional treatments.…”

“…What's more, RNA can be synthesized through chemical methods, which is more cost-effective and convenient than other biologics. Therefore, RNA therapeutic drugs have significant potential in application because of their high efficacy, specificity and wide range of application 20 .…”

“…Due to its poor stability, RNA can be easily degraded in organisms by ribonuclease (RNase), making the biological half-life too short. The low efficiency of cellular uptake makes it difficult for the drugs to get into the target cells 20 . Besides, RNA itself is potentially immunogenic and likely to have off-target effects 51 , 52 .…”

“…Drug delivery system or the carrier technology can help drugs be taken up by cells more efficiently, reach the therapeutic targets more directly, enhance the targeting effect and biological activity, and prevent the drugs from being degraded by nucleases 186 . Liposomes, cationic polymer complexes, dendrimers, polymer microsomes, peptide protein delivery vehicles, and nanoparticles are all thought to be suitable choices of delivery systems 20 . Among them, nanostructure lipid carrier (NLC) is considered the most promising drug delivery system at present.…”