Duplex structure of double-stranded RNA provides stability against hydrolysis relative to single-stranded RNA

Ke Zhang, Joseph Hodge, Anamika Chatterjee, Tae Seok Moon, Kimberly M. Parker

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Phosphodiester bonds in the backbones of double-stranded (ds)RNA and single-stranded (ss)RNA are known to undergo alkaline hydrolysis. Consequently, dsRNA agents used in emerging RNA interference (RNAi) products have been assumed to exhibit low chemical persistence in solutions. However, the impact of the duplex structure of dsRNA on alkaline hydrolysis has not yet been evaluated. In this study, we demonstrated that dsRNA undergoes orders-of-magnitude slower alkaline hydrolysis than ssRNA. Furthermore, we observed that dsRNA remains intact for multiple months at neutral pH, challenging the assumption that dsRNA is chemically unstable. In systems enabling both enzymatic degradation and alkaline hydrolysis of dsRNA, we found that increasing pH effectively attenuated enzymatic degradation without inducing alkaline hydrolysis that was observed for ssRNA. Overall, our findings demonstrated, for the first time, that key degradation pathways of dsRNA significantly differ from those of ssRNA. Consideration of the unique properties of dsRNA will enable greater control of dsRNA stability during the application of emerging RNAi technology and more accurate assessment of its fate in environmental and biological systems, as well as provide insights into broader application areas including dsRNA isolation, detection and inactivation of dsRNA viruses, and prebiotic molecular evolution.

Original languageEnglish
Pages (from-to)8045-8053
Number of pages9
JournalEnvironmental Science and Technology
Issue number12
StatePublished - Jun 15 2021


  • Alkaline hydrolysis
  • Base-catalyzed hydrolysis
  • Double-stranded RNA
  • Secondary structure
  • Single-stranded RNA


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