Periodic-shRNA molecules are capable of gene silencing, cytotoxicity and innate immune activation in cancer cells
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Shopsowitz-2016-Periodic-shRNA molec.pdf
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Author(s)
Wu, Connie
Shopsowitz, Kevin
Liu, Gina S. Y.
Hammond, Paula T
Dreaden, Erik
Date Issued
December 2015
Journal
Nucleic Acids Research
Publisher
Oxford University Press
Citation
Shopsowitz, Kevin E., Connie Wu, Gina Liu, Erik C. Dreaden, and Paula T. Hammond. “Periodic-shRNA Molecules Are Capable of Gene Silencing, Cytotoxicity and Innate Immune Activation in Cancer Cells.” Nucleic Acids Research 44, no. 2 (December 23, 2015): 545–557.
Version
Final published version
Abstract
Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activation of pattern recognition receptors; however, synthetic versions of these molecules are mostly limited to simple sequences like poly-I:C and poly-A:U. Here we show that large RNA molecules generated by rolling circle transcription fold into periodic-shRNA (p-shRNA) structures and cause potent cytotoxicity and gene silencing when delivered to cancer cells. We determined structural requirements for the dumbbell templates used to synthesize p-shRNA, and showed that these molecules likely adopt a co-transcriptionally folded structure. The cytotoxicity of p-shRNA was robustly observed across four different cancer cell lines using two different delivery systems. Despite having a considerably different folded structure than conventional dsRNA, the cytotoxicity of p-shRNA was either equal to or substantially greater than that of poly-I:C depending on the delivery vehicle. Furthermore, p-shRNA caused greater NF-κB activation in SKOV3 cells compared to poly-I:C, indicating that it is a powerful activator of innate immunity. The tuneable sequence and combined gene silencing, immunostimulatory and cytotoxic capacity of p-shRNA make it an attractive platform for cancer immunotherapy.
MIT Department
Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1093/nar/gkv1488
