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

78 Scopus citations


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
Issue number9
StatePublished - Sep 2021


  • Animals
  • Colitis/genetics
  • Gene Expression Regulation/drug effects
  • Gene Silencing
  • Humans
  • Integrin alpha4/chemistry
  • Integrin beta Chains/chemistry
  • Lipids/chemistry
  • Liver/drug effects
  • Mice
  • Nanoparticles/chemistry
  • RNA, Small Interfering/genetics

ASJC Scopus subject areas

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


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