In vivo hematopoietic stem cell modification by mRNA delivery

Science. 2023 Jul 28;381(6656):436-443. doi: 10.1126/science.ade6967. Epub 2023 Jul 27.


Hematopoietic stem cells (HSCs) are the source of all blood cells over an individual's lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP-messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti-human CD117/LNP-based editing system yielded near-complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT.

MeSH terms

  • Animals
  • Gene Editing* / methods
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells* / metabolism
  • Humans
  • Mice
  • Proto-Oncogene Proteins c-kit* / genetics
  • RNA, Messenger* / genetics


  • Lipid Nanoparticles
  • Proto-Oncogene Proteins c-kit
  • RNA, Messenger
  • PUMA protein, mouse