The effector mechanism of siRNA spherical nucleic acids

Gokay Yamankurt, Robert J. Stawicki, Diana M. Posadas, Joseph Q. Nguyen, Richard W. Carthew, Chad A. Mirkin*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Spherical nucleic acids (SNAs) are nanostructures formed by chemically conjugating short linear strands of oligonucleotides to a nanoparticle template. When made with modified small interfering RNA (siRNA) duplexes, SNAs act as single-entity transfection and gene silencing agents and have been used as lead therapeutic constructs in several disease models. However, the manner in which modified siRNA duplex strands that comprise the SNA lead to gene silencing is not understood. Herein, a systematic analysis of siRNA biochemistry involving SNAs shows that Dicer cleaves the modified siRNA duplex from the surface of the nanoparticle, and the liberated siRNA subsequently functions in a way that is dependent on the canonical RNA interference mechanism. By leveraging this understanding, a class of SNAs was chemically designed which increases the siRNA content by an order of magnitude through covalent attachment of each strand of the duplex. As a consequence of increased nucleic acid content, this nanostructure architecture exhibits less cell cytotoxicity than conventional SNAs without a decrease in siRNA activity.

Original languageEnglish (US)
Pages (from-to)1312-1320
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number3
DOIs
StatePublished - Jan 21 2020

Keywords

  • Gene regulation
  • SiRNA processing
  • Spherical nucleic acids

ASJC Scopus subject areas

  • General

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