Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche

Abstract

Bone marrow hematopoietic stem and progenitor cells (HSPC) give rise to billions of blood cells every day. Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulates HSC maintenance and blood cell traffic. Here we report the design of a lipid/polymer nanoparticle that delivers siRNA to the hematopoietic stem cell niche in vivo. Newly identified nanoparticles induced potent gene silencing in BMECs. We demonstrate RNAi control of cellular release from the hematopoietic niche by silencing the proteins Sdf1 and Mcp1, which enhanced and inhibited bone marrow HSPC and leukocyte release, respectively. In mice with myocardial infarction, nanoparticle-mediated inhibition of cell release from the hematopoietic niche reduced leukocytes in the diseased heart, improved infarct healing and reduced heart failure. These nanoparticles target the hematopoietic niche in vivo and may be utilized to probe fundamental hematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.