Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.

造血干细胞（HSC）的治疗性基因组编辑将为多种疾病提供持久的治疗方法。然而，将基因药物体内递送至造血干细胞仍然具有挑战性，特别是在患病和恶性环境中。在这里，我们报告了一系列骨髓归巢脂质纳米粒子，它们将 mRNA 传递到骨髓中至少 14 种独特的细胞类型，包括健康和患病的 HSC、白血病干细胞、B 细胞、T 细胞、巨噬细胞和白血病细胞。在表达人类镰状细胞病表型的小鼠模型中实现了 CRISPR/Cas 和碱基编辑，以实现潜在的胎儿血红蛋白重新激活以及从镰状细胞等位基因向非镰状细胞等位基因的转化。骨髓归巢脂质纳米颗粒还能够在骨髓移植的白血病干细胞和白血病细胞中实现 Cre 重组酶介导的基因缺失。我们证明，可以使用骨髓归巢脂质纳米颗粒来编辑骨髓生态位中的多种细胞类型。