Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics

Niels Dammes, Meir Goldsmith, Srinivas Ramishetti, Jason L.J. Dearling, Nuphar Veiga, Alan B. Packard, Dan Peer

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles are one of the most advanced non-viral clinically approved nucleic-acid delivery systems. Yet lipid nanoparticles accumulate naturally in liver cells upon intravenous administration, and hence, there is an urgent need to enhance uptake by other cell types. Here we use a conformation-sensitive targeting strategy to achieve in vivo gene silencing in a selective subset of leukocytes and show potential therapeutic applications in a murine model of colitis. In particular, by targeting the high-affinity conformation of α4β7 integrin, which is a hallmark of inflammatory gut-homing leukocytes, we silenced interferon-γ in the gut, resulting in an improved therapeutic outcome in experimental colitis. The lipid nanoparticles did not induce adverse immune activation or liver toxicity. These results suggest that our lipid nanoparticle targeting strategy might be applied for selective delivery of payloads to other conformation-sensitive targets.

Original languageEnglish (US)
Pages (from-to)1030-1038
Number of pages9
JournalNature Nanotechnology
Volume16
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Bioengineering
  • Atomic and Molecular Physics, and Optics
  • Biomedical Engineering
  • Materials Science(all)
  • Condensed Matter Physics
  • Electrical and Electronic Engineering

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