Silencing of proinflammatory genes targeted to peritoneal-residing macrophages using siRNA encapsulated in biodegradable microspheres

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

One of the more substantial hurdles to be overcome in realizing the exciting potential of siRNA molecules as therapeutic agents for a wide range of diseases is the intact delivery of the active molecule into its target cell. Here, we present a platform for in vitro and in vivo delivery and intracellular release of siRNA in peritoneal macrophages (Mφ{symbol}s). The delivery platform is based on the encapsulation of siRNA in biodegradable poly(d,l-lactide) (PLA) microspheres, which are targeted to Mφ{symbol}s by the simple principle of size exclusion. Proof of concept was achieved using siRNAs targeting TNFα and CD86 in macrophages. We show that the release of the siRNA in peritoneal-derived macrophages in vitro occurs intracellularly, and is abrogated by cytochalasin B, a phagocytosis inhibitor. Silencing in these cells is potent and lasts for at least one week. In vivo, we prove that siRNA encapsulated in biodegradable PLA microspheres can be delivered to peritoneal-residing Mφ{symbol}s and can induce potent silencing of TNFα secretion for at least one week. The PLA microspheres hold great potential for in vivo use, due to their biocompatibility and degradability, and can potentially be used for in vivo immunomodulation of Mφ{symbol}s for treatment of autoimmune and chronic inflammatory conditions.

Original languageEnglish
Pages (from-to)2627-2636
Number of pages10
JournalBiomaterials
Volume31
Issue number9
DOIs
StatePublished - 1 Mar 2010

Keywords

  • Biodegradable microspheres
  • Immunomodulation
  • Macrophage
  • siRNA delivery

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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