Bone Marrow Homing Lipid Nanoparticles for Genome Editing in Diseased and Malignant Hematopoietic Stem Cells

Therapeutic genome editing of hematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, 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 sickle to non-sickle allele conversion. 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.