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
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 Cancer Center Program > Gene Regulation and Cell Proliferation CSHL labs > Joshua-Tor lab CSHL Cancer Center Program > Gene Regulation and Inheritance Program |
| Depositing User: | Matt Covey |
| Date: | 5 February 2018 |
| Date Deposited: | 20 Feb 2018 21:24 |
| Last Modified: | 05 Nov 2020 22:35 |
| PMCID: | PMC5866582 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36071 |
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