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Rationally Designed Polycationic Carriers for Potent Polymeric siRNA-Mediated Gene Silencing

Author(s)
Wu, Connie; Li, Jiahe; Wang, Wade; Hammond, Paula T
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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)
Date issued
2018-06-26
URI
https://hdl.handle.net/1721.1/122901
Department
David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Chemical Engineering; Massachusetts Institute of Technology. Department of Chemistry
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
ISSN
1936-0851
1936-086X

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