Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
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The main data supporting the results in this study are available within this paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding authors on reasonable request.
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This work was funded in part by the National Institutes of Health (NIH) (nos. HL125428, HL131495 and T32HL076136), the European Union’s Horizon 2020 research and innovation programme (grant no. 667837) and the MGH Research Scholar Program. M.K.-G., M.J.S., D.R., S.C. and F.F.H. were supported by the Deutsche Forschungsgemeinschaft (nos. KR4613/1-1, SCHL 2221/1-1, RO5071/1-1, CR603/11 and HO5279/1-2). M.J.M. is supported by a Burroughs Wellcome Fund Career Award at the Scientific Interface, a Ruth L. Kirschstein National Research Service Award (no. F32CA200351) from the NIH, a fellowship from the Max Planck Society and a grant from the Burroughs Wellcome Fund (no. 1015145). P.P.G.G. is supported by a CNPq postdoctoral fellowship (no. 202856/2015-1) and a Fundação Estudar fellowship. This work is further supported in part by NIH grant no. R37-EB000244-30 (to R.L.), NIH contract no. HHSN268201000045C (to R.L.), a Koch–Prostate Cancer Foundation Award in Nanotherapeutics (to R.L.), the Koch Institute Marble Center for Cancer Nanomedicine and a Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. We acknowledge the use of resources at the Koch Institute Swanson Biotechnology Center (and technical support), as well as the W.M. Keck Biological Imaging Facility (Whitehead Institute) and thank S. Mordecai at the flow, image and mass cytometry core of the MGH Department of Pathology. We thank K. Joyes for editing the manuscript.
R.L. has served as an advisor to Alnylam Pharmaceuticals. For a list of entities with which R.L. is involved, compensated or uncompensated, see www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0. M.N. has received consulting fees unrelated to this work from Verseau, Gimv and IMF Therapeutics. The remaining authors declare no competing interests.
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Krohn-Grimberghe, M., Mitchell, M.J., Schloss, M.J. et al. Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. Nat Biomed Eng 4, 1076–1089 (2020). https://doi.org/10.1038/s41551-020-00623-7
Nature Biomedical Engineering (2020)