Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 3, Pages 1312-1320Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1915907117
Keywords
spherical nucleic acids; siRNA processing; gene regulation
Categories
Funding
- National Cancer Institute [U54CA199091, P50CA221747, R01CA208783]
- National Institute of General Medical Sciences [R35GM118144]
- Prostate Cancer Foundation
- Movember Foundation [17CHAL08]
- Chemistry of Life Processes at Northwestern University [T32GM105538]
- Pew Latin American Postdoctoral Fellowship
- Northwestern University
- State of Illinois
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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.
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