MRNA Nanoparticles Reprogram Bone Marrow in Mice

Bone marrow transplantation can be used to treat blood cell malignancies and sometimes to cure certain non-malignant blood cell disorders, but finding or creating appropriate donor bone marrow cells and preparing the body to receive that donation remain challenging obstacles for the therapy. Now, Laura Breda and colleagues have developed a strategy to deliver mRNA directly into bone marrow stem cells where it can edit genetic defects and help repopulate the bone marrow with healthy blood cells. The technique can also be used to deplete the bone marrow niche of hematopoietic stem cells in preparation for new stem cells. The researchers demonstrated the technique in the bone marrow of living mice and in human hematopoietic stem cells taken from four patients with sickle cell disorder. In the human samples, Breda et al. were able to correct the sickle cell genetic defect, leading to a near absence of sickling cells. Together, the findings offer a potential route for gene editing of bone marrow cells without the need for the usual transplantation processes of finding a suitable bone marrow donor or re-engineering a patient's own cells outside the body before re-transplantation, and without the need for toxic chemotherapy or radiation to prepare the bone marrow niche before transplantation. The new gene editing system consists of mRNA within a lipid nanocapsule – similar to the technology used in mRNA SARS-CoV-2 vaccines – that contains an antibody that targets the nanocapsules specifically to hematopoietic stem cells. In a related Perspective, Samuele Ferrari and Luigi Naldini caution that there may be "a long, winding, mountain road" to implementing this technique in humans, and that further preclinical studies will be needed to confirm its safety and effectiveness in non-human primates and humanized stem cell niches.