Protein-RNA interaction guided chemical modification of Dicer substrate RNA nanostructures for superior in vivo gene silencing

Bora Jang, Hyejin Jang, Hyunsook Kim, Minjeong Kim, Michaela Jeong, Gyeong Seok Lee, Kyuri Lee, Hyukjin Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Dicer substrate RNA is an alternative gene silencing agent to canonical siRNA. Enhanced in vitro gene silencing can be achieved with RNA substrates by facilitating Ago2 loading of dsRNA after Dicer processing. However, the in vivo use of Dicer substrate RNA has been hindered by its instability and immunogenicity in the body due to the lack of proper chemical modification in the structure. Here, we report a universal chemical modification approach for Dicer substrate RNA nanostructures by optimizing protein-RNA interactions in the RNAi pathway. Proteins involved in the RNAi pathway were utilized for evaluating their recognition and binding of substrate RNA. It was found that conventional chemical modifications could severely affect the binding and processing of substrate RNA, consequently reducing RNAi activity. Protein-RNA interaction guided chemical modification was introduced to RNA nanostructures, and their gene silencing activity was assessed. The optimized RNA nanostructures showed excellent binding and processability with RNA binding proteins and offered the enhancement of in vivo EC50 up to 1/8 of its native form.

Original languageEnglish
Pages (from-to)57-65
Number of pages9
JournalJournal of Controlled Release
Volume343
DOIs
StatePublished - Mar 2022

Keywords

  • Chemical modification
  • Dicer substrate RNA
  • Gene silencing
  • Gene therapy
  • RNA nanostructures
  • siRNA

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