Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference

Li, J., Wu, C., Wang, W., He, Y., Elkayam, E., Joshua-Tor, L., Hammond, P. T. (February 2018) Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference. Proc Natl Acad Sci U S A, 115 (12). E2696-E2705. ISSN 0027-8424

URL: https://www.ncbi.nlm.nih.gov/pubmed/29432194
DOI: 10.1073/pnas.1719565115

Abstract

Small interfering RNA (siRNA) represents a promising class of inhibitors in both fundamental research and the clinic. Numerous delivery vehicles have been developed to facilitate siRNA delivery. Nevertheless, achieving highly potent RNA interference (RNAi) toward clinical translation requires efficient formation of RNA-induced gene-silencing complex (RISC) in the cytoplasm. Here we coencapsulate siRNA and the central RNAi effector protein Argonaute 2 (Ago2) via different delivery carriers as a platform to augment RNAi. The physical clustering between siRNA and Ago2 is found to be indispensable for enhanced RNAi. Moreover, by utilizing polyamines bearing the same backbone but distinct cationic side-group arrangements of ethylene diamine repeats as the delivery vehicles, we find that the molecular structure of these polyamines modulates the degree of siRNA/Ago2-mediated improvement of RNAi. We apply this strategy to silence the oncogene STAT3 and significantly prolong survival in mice challenged with melanoma. Our findings suggest a paradigm for RNAi via the synergistic coassembly of RNA with helper proteins.

Item Type: Paper
Uncontrolled Keywords: Argonaute RNA interference gene delivery polyamines siRNA on this work has been filed.
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > argonaute proteins
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > siRNA
CSHL Authors:
Communities: CSHL labs > Joshua-Tor lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 5 February 2018
Date Deposited: 20 Feb 2018 21:24
Last Modified: 12 Jun 2018 19:14
PMCID: PMC5866582
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36071

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