A bridge to silencing: Co-assembling anionic nanoparticles of siRNA and hyaluronan sulfate via calcium ion bridges

Efrat Forti, Olga Kryukov, Edan Elovic, Matan Goldshtein, Efrat Korin, Gal Margolis, Shani Felder, Emil Ruvinov, Smadar Cohen

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Therapeutic implementation of RNA interference (RNAi) through delivery of short interfering RNA (siRNA) is still facing several critical hurdles, which mostly can be solved through the use of an efficient delivery system. We hereby introduce anionic siRNA nanoparticles (NPs) co-assembled by the electrostatic interactions of the semi-synthetic polysaccharide hyaluronan-sulfate (HAS), with siRNA, mediated by calcium ion bridges. The NPs have an average size of 130 nm and a mild (- 10 mV) negative surface charge. Transmission electron microscopy (TEM) using gold-labeled components and X-ray photoelectron spectroscopy (XPS) demonstrated the spatial organization of siRNA molecules in the particle core, surrounded by a layer of HAS. The anionic NPs efficiently encapsulated siRNA, were stable in physiological-relevant environments and were cytocompatible, not affecting cell viability or homeostasis. Efficient cellular uptake of the anionic siRNA NPs, associated with potent gene silencing (> 80%), was observed across multiple cell types, including murine primary peritoneal macrophages and human hepatocellular carcinoma cells. In a clinically-relevant model of acute inflammatory response in IL-6-stimulated human hepatocytes, STAT3 silencing induced by HAS-Ca2 +-siRNA NPs resulted in marked decrease in the total and activated STAT3 protein levels, as well as in the expression levels of downstream acute phase response genes. Collectively, anionic NPs prove to be an efficient and cytocompatible delivery system for siRNA.

Original languageEnglish
Pages (from-to)215-227
Number of pages13
JournalJournal of Controlled Release
Volume232
DOIs
StatePublished - 28 Jun 2016

Keywords

  • Acute phase response
  • Anionic polymer
  • Gene silencing
  • Hepatocytes
  • Hyaluronan-sulfate
  • Transfection
  • siRNA delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

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