Chemical modification is the key to improving pairing affinity, metabolic stability, and cellular uptake of RNA and absolutely essential in the discovery and development of highly active RNA therapeutic candidates. Therefore, many of the chemical modifications have been developed to introducing into RNA oligo to improve their thermal stability, serum stability, cellular activity, or pharmacokinetic properties. For instance, the replacement of phosphodiester with phosphorothioate (PS) linkages will reduce cleavage by nucleases and increase the half-life of oligonucleotides in vivo.