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 Wang¹, Yan Cheng¹, Da Xie⁴, Yang Gui⁴, Haokun Zhang⁴, Changrui Feng⁴, Feiyan Zhao¹, Wendan Ren⁴, Gongrui Sun¹, Yang Yang⁵, Lin Li⁶, Yongrong Lai⁵, Bin Fu⁷, Yuming Lu^{8

9}, Zi Jun Wang¹⁰, Yuxuan Wu^{11

12}

Affiliations

¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
² Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
³ NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
⁴ YolTech Therapeutics, Shanghai, China.
⁵ Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁶ School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
⁷ Xiangya Hospital, Central South University, Hunan, China.
⁸ YolTech Therapeutics, Shanghai, China. luymin@sjtu.edu.cn.
⁹ School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China. luymin@sjtu.edu.cn.
¹⁰ YolTech Therapeutics, Shanghai, China. zjwang@yoltx.com.
¹¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. yxwu@bio.ecnu.edu.cn.
¹² YolTech Therapeutics, Shanghai, China. yxwu@bio.ecnu.edu.cn.

^# Contributed equally.

PMID: 40796944
DOI: 10.1038/s41551-025-01480-y

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

Saijuan Xu et al. Nat Biomed Eng. 2025.

. 2025 Aug 12.

doi: 10.1038/s41551-025-01480-y. Online ahead of print.

Authors

Affiliations

¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
² Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
³ NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
⁴ YolTech Therapeutics, Shanghai, China.
⁵ Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁶ School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
⁷ Xiangya Hospital, Central South University, Hunan, China.
⁸ YolTech Therapeutics, Shanghai, China. luymin@sjtu.edu.cn.
⁹ School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China. luymin@sjtu.edu.cn.
¹⁰ YolTech Therapeutics, Shanghai, China. zjwang@yoltx.com.
¹¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. yxwu@bio.ecnu.edu.cn.
¹² YolTech Therapeutics, Shanghai, China. yxwu@bio.ecnu.edu.cn.

^# Contributed equally.

PMID: 40796944
DOI: 10.1038/s41551-025-01480-y

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.

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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

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

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