Rationally Designed Polycationic Carriers for Potent Polymeric siRNA-Mediated Gene Silencing
Name
nihms-987858.pdf
Description
Accepted version
Size
1.7 MB
Format
Adobe PDF
Checksum (MD5)
c7c0a2df1953bd8d61421c66bb452a0c
Author(s)
Wu, Connie
Li, Jiahe
Wang, Wade
Hammond, Paula T
Date Issued
June 26, 2018
Journal
ACS Nano
Publisher
American Chemical Society
Citation
Wu, Connie et al. "Rationally designed polycationic carriers for potent polymeric siRNA-mediated gene silencing." ACS Nano 12, 7 (2018): 6504–6514 © 2018 Publisher
Version
Author's final manuscript
Abstract
The delivery of small interfering RNA (siRNA) remains a major hurdle for the clinical translation of RNA interference (RNAi) therapeutics. Because of its low valency and rigid nature, siRNA typically requires high excesses of cationic delivery materials to package it stably and deliver it to the cytoplasm of target cells, resulting in high toxicities and inefficient gene silencing in vivo. To address these challenges, we pair a polymeric form of siRNA, p-shRNA, with optimized biodegradable polycations to form stable complexes that induce far more potent gene silencing than with siRNA complexes. Furthermore, we unveil a set of design rules governing p-shRNA delivery, using degradable polycations containing hydrophobic and stabilizing polyethylene glycol domains that enable both stable condensation and efficient release inside cells. We demonstrate the therapeutic potential of this approach by silencing the oncogene STAT3 in a well-established B16F10 mouse melanoma model to significantly prolong survival. By blending nucleic acid engineering and polymer design, our system provides a potentially translatable platform for RNAi-based therapies. Keywords: RNA interference; polycation; gene delivery; siRNA; poly(beta-amino ester)
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/acsnano.7b08777
