Delivery of siRNAs to dendritic cells using DEC205-targeted lipid nanoparticles to inhibit immune responses

Joseph A. Katakowski, Gayatri Mukherjee, Samantha E. Wilner, Keith E. Maier, Michael Travis Harrison, Teresa P. DiLorenzo, Matthew Levy, Deborah Palliser

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving "undruggable" targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205 + DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR.

Original languageEnglish (US)
Pages (from-to)146-155
Number of pages10
JournalMolecular Therapy
Volume24
Issue number1
DOIs
StatePublished - Feb 1 2016

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ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Katakowski, J. A., Mukherjee, G., Wilner, S. E., Maier, K. E., Harrison, M. T., DiLorenzo, T. P., Levy, M., & Palliser, D. (2016). Delivery of siRNAs to dendritic cells using DEC205-targeted lipid nanoparticles to inhibit immune responses. Molecular Therapy, 24(1), 146-155. https://doi.org/10.1038/mt.2015.175