本期文章：《科学》：Volume 381 Issue 6656

近日，美国宾夕法尼亚大学Hamideh Parhiz等研究人员合作通过mRNA递送对体内造血干细胞进行改造。该项研究成果发表在2023年7月28日出版的《科学》杂志上。

研究人员开发了CD117/LNP-信使RNA（mRNA），这是一种封装mRNA的脂质纳米颗粒（LNP），可靶向造血干细胞上的干细胞因子受体（CD117）。基于抗人类CD117/LNP编辑系统的递送几乎完全纠正了造血镰状细胞。此外，用CD117/LNP在体内传递促凋亡的PUMA（p53上调凋亡调节因子）mRNA会影响造血干细胞的功能，并允许造血干细胞移植（HSCT）的非基因毒性调整。

体内靶向造血干细胞的能力为HSCT提供了一种非基因毒性调整方案，这一平台可作为体内基因组编辑治疗遗传疾病的基础，从而消除造血干细胞移植的需要。

据悉，造血干细胞是人一生中所有血细胞的来源。通过HSCT，人们可以用基因工程造血干细胞或健康造血干细胞替代患病的造血干细胞。然而，目前的方案有很大的副作用，而且使用机会有限。

附：英文原文

Title: In vivo hematopoietic stem cell modification by mRNA delivery

Author: Laura Breda, Tyler E. Papp, Michael P. Triebwasser, Amir Yadegari, Megan T. Fedorky, Naoto Tanaka, Osheiza Abdulmalik, Giulia Pavani, Yongping Wang, Stephan A. Grupp, Stella T. Chou, Houping Ni, Barbara L. Mui, Ying K. Tam, Drew Weissman, Stefano Rivella, Hamideh Parhiz

Issue&Volume: 2023-07-28

Abstract: 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.

DOI: ade6967