Rationally Designed Polycationic Carriers for Potent Polymeric siRNA-Mediated Gene Silencing
Year: 2018
Type: article
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.
Source: ACS Nano
Authors: Connie Wu, Jiahe Li, Wade Wang, Paula T. Hammond
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, Virginia and D.K. Ludwig Fund for Cancer Research, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Ludwig Center at Harvard, National Cancer Institute, Division of Graduate Education, Congressionally Directed Medical Research Programs
OpenAlex ID: W2811477937