In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles

Nano Lett. 2023 Apr 12;23(7):2938-2944. doi: 10.1021/acs.nanolett.3c00304. Epub 2023 Mar 29.

Abstract

Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg-1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.

Keywords: RNA; antibody targeting; blood disorders; hematopoietic stem cells; lipid nanoparticle.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Hematopoietic Stem Cell Transplantation* / methods
  • Hematopoietic Stem Cells / metabolism
  • RNA, Messenger / metabolism
  • RNA, Small Interfering

Substances

  • Lipid Nanoparticles
  • RNA, Small Interfering
  • RNA, Messenger