Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2026 Mar;10(3):473-489.
doi: 10.1038/s41551-025-01480-y. Epub 2025 Aug 12.

In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery

Saijuan Xu #  1 , Dan Liang #  2   3 , Qiudao Wang  1 , Yan Cheng  1 , Da Xie  4 , Yang Gui  4 , Haokun Zhang  4 , Changrui Feng  4 , Feiyan Zhao  1 , Wendan Ren  4 , Gongrui Sun  1 , Yang Yang  5 , Lin Li  6 , Yongrong Lai  5 , Bin Fu  7 , Yuming Lu  8   9 , Zi Jun Wang  10 , Yuxuan Wu  11   12
Affiliations

In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery

Saijuan Xu et al. Nat Biomed Eng. 2026 Mar.

Abstract

Ex vivo autologous haematopoietic stem cell (HSC) gene therapy provides a promising treatment option for haematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and major side effects. Here we develop antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the γ-globin gene (HBG1/2) promoter target in human HSCs to reactivate fetal haemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG1/2 in transfusion-dependent β-thalassaemia (TDT) patient-derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicates that using LNPs for genome editor delivery achieves efficient editing of endogenous genes of human HSCs. This non-viral delivery system eliminates the need for collecting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders such as sickle cell disease and TDT.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Y. Lu, Z.J.W. and Y.W. are scientific co-founders at YolTech Therapeutics. D.X., W.R., Y.G., H.Z. and C.F. are employees of YolTech Therapeutics. YolTech Therapeutics has filed patents (CN114989182A, CN116162071A, PCT/CN2023/100791, PCT/CN2023/100823 and PCT/CN2023/106421) on the technology described in this paper. The other authors declare no competing interests.

References

    1. Esrick, E. B. et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N. Engl. J. Med. 384, 205–215 (2021). - PubMed - DOI
    1. Frangoul, H. et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 384, 252–260 (2021). - PubMed - DOI
    1. Fu, B. et al. CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric β0/β0 transfusion-dependent β-thalassemia. Nat. Med. 28, 1573–1580 (2022). - PubMed - DOI
    1. Germino-Watnick, P. et al. Hematopoietic stem cell gene-addition/editing therapy in sickle cell disease. Cells 11, 1843 (2022). - PubMed - PMC - DOI
    1. Cavazzana, M., Bushman, F. D., Miccio, A., Andre-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. 18, 447–462 (2019). - PubMed - DOI

MeSH terms

LinkOut - more resources