A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

Srinivas Ramishetti, Inbal Hazan-Halevy, Ramesh Palakuri, Sushmita Chatterjee, Somu Naidu Gonna, Niels Dammes, Inbar Freilich, Luba Kolik Shmuel, Dganit Danino, Dan Peer

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The previous generation of ionizable lipids varies in linker moieties, which greatly influences in vivo gene silencing efficiency. Here novel ionizable amino lipids based on the linker moieties such as hydrazine, hydroxylamine, and ethanolamine are designed and synthesized. These lipids are formulated into LNPs and screened for their efficiency to deliver siRNAs into leukocytes, which are among the hardest to transfect cell types. Two potent lipids based on their in vitro gene silencing efficiencies are also identified. These lipids are further evaluated for their biodistribution profile, efficient gene silencing, liver toxicity, and potential immune activation in mice. A robust gene silencing is also found in primary lymphocytes when one of these lipids is formulated into LNPs with a pan leukocyte selective targeting agent (β7 integrin). Taken together, these lipids have the potential to open new avenues in delivering RNAs into leukocytes.

Original languageEnglish (US)
Article number1906128
JournalAdvanced Materials
Volume32
Issue number12
DOIs
StatePublished - Mar 1 2020

Keywords

  • T-lymphocytes
  • gene silencing
  • lipid nanoparticles
  • synthetic small interfering RNA
  • targeted delivery

ASJC Scopus subject areas

  • Materials Science(all)
  • Mechanics of Materials
  • Mechanical Engineering

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    Ramishetti, S., Hazan-Halevy, I., Palakuri, R., Chatterjee, S., Naidu Gonna, S., Dammes, N., Freilich, I., Kolik Shmuel, L., Danino, D., & Peer, D. (2020). A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes. Advanced Materials, 32(12), [1906128]. https://doi.org/10.1002/adma.201906128