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

Marvin Krohn-Grimberghe; Michael J. Mitchell; Maximilian J. Schloss; Omar F. Khan; Gabriel Courties; Pedro P.G. Guimaraes; David Rohde; Sebastian Cremer; Piotr S. Kowalski; Yuan Sun; Mingchee Tan; Jamie Webster; Karin Wang; Yoshiko Iwamoto; Stephen P. Schmidt; Gregory R. Wojtkiewicz; Ribhu Nayar; Vanessa Frodermann; Maarten Hulsmans; Amanda Chung; Friedrich Felix Hoyer; Filip K. Swirski; Robert Langer; Daniel G. Anderson; Matthias Nahrendorf

doi:10.1038/s41551-020-00623-7

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

Marvin Krohn-Grimberghe
, Michael J. Mitchell
, Maximilian J. Schloss
, Omar F. Khan
, Gabriel Courties
, Pedro P.G. Guimaraes
, David Rohde
, Sebastian Cremer
, Piotr S. Kowalski
, Yuan Sun
, Mingchee Tan
, Jamie Webster
, Karin Wang
, Yoshiko Iwamoto
, Stephen P. Schmidt
, Gregory R. Wojtkiewicz
, Ribhu Nayar
, Vanessa Frodermann
, Maarten Hulsmans
, Amanda Chung

Friedrich Felix Hoyer, Filip K. Swirski, Robert Langer, Daniel G. Anderson, Matthias Nahrendorf

Massachusetts General Hospital
University of Freiburg
Massachusetts Institute of Technology
University of Pennsylvania
Harvard University
University of Würzburg

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1076-1089
Number of pages	14
Journal	Nature Biomedical Engineering
Volume	4
Issue number	11
DOIs	https://doi.org/10.1038/s41551-020-00623-7
Publication status	Published - 1 Nov 2020
Externally published	Yes

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SDG 3 Good Health and Well-being

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Krohn-Grimberghe, M., Mitchell, M. J., Schloss, M. J., Khan, O. F., Courties, G., Guimaraes, P. P. G., Rohde, D., Cremer, S., Kowalski, P. S., Sun, Y., Tan, M., Webster, J., Wang, K., Iwamoto, Y., Schmidt, S. P., Wojtkiewicz, G. R., Nayar, R., Frodermann, V., Hulsmans, M., ... Nahrendorf, M. (2020). Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. Nature Biomedical Engineering, 4(11), 1076-1089. https://doi.org/10.1038/s41551-020-00623-7

@article{a64fafd98c2a416889fcfcd5ce217e1e,

title = "Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche",

abstract = "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.",

author = "Marvin Krohn-Grimberghe and Mitchell, \{Michael J.\} and Schloss, \{Maximilian J.\} and Khan, \{Omar F.\} and Gabriel Courties and Guimaraes, \{Pedro P.G.\} and David Rohde and Sebastian Cremer and Kowalski, \{Piotr S.\} and Yuan Sun and Mingchee Tan and Jamie Webster and Karin Wang and Yoshiko Iwamoto and Schmidt, \{Stephen P.\} and Wojtkiewicz, \{Gregory R.\} and Ribhu Nayar and Vanessa Frodermann and Maarten Hulsmans and Amanda Chung and Hoyer, \{Friedrich Felix\} and Swirski, \{Filip K.\} and Robert Langer and Anderson, \{Daniel G.\} and Matthias Nahrendorf",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = nov,

day = "1",

doi = "10.1038/s41551-020-00623-7",

language = "English",

volume = "4",

pages = "1076--1089",

journal = "Nature Biomedical Engineering",

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Krohn-Grimberghe, M, Mitchell, MJ, Schloss, MJ, Khan, OF, Courties, G, Guimaraes, PPG, Rohde, D, Cremer, S, Kowalski, PS, Sun, Y, Tan, M, Webster, J, Wang, K, Iwamoto, Y, Schmidt, SP, Wojtkiewicz, GR, Nayar, R, Frodermann, V, Hulsmans, M, Chung, A, Hoyer, FF, Swirski, FK, Langer, R, Anderson, DG & Nahrendorf, M 2020, 'Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche', Nature Biomedical Engineering, vol. 4, no. 11, pp. 1076-1089. https://doi.org/10.1038/s41551-020-00623-7

TY - JOUR

T1 - Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche

AU - Krohn-Grimberghe, Marvin

AU - Mitchell, Michael J.

AU - Schloss, Maximilian J.

AU - Khan, Omar F.

AU - Courties, Gabriel

AU - Guimaraes, Pedro P.G.

AU - Rohde, David

AU - Cremer, Sebastian

AU - Kowalski, Piotr S.

AU - Sun, Yuan

AU - Tan, Mingchee

AU - Webster, Jamie

AU - Wang, Karin

AU - Iwamoto, Yoshiko

AU - Schmidt, Stephen P.

AU - Wojtkiewicz, Gregory R.

AU - Nayar, Ribhu

AU - Frodermann, Vanessa

AU - Hulsmans, Maarten

AU - Chung, Amanda

AU - Hoyer, Friedrich Felix

AU - Swirski, Filip K.

AU - Langer, Robert

AU - Anderson, Daniel G.

AU - Nahrendorf, Matthias

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85092088005

U2 - 10.1038/s41551-020-00623-7

DO - 10.1038/s41551-020-00623-7

M3 - Article

C2 - 33020600

AN - SCOPUS:85092088005

SN - 2157-846X

VL - 4

SP - 1076

EP - 1089

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

IS - 11

ER -

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

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