Therapeutic siRNA silencing in inflammatory monocytes in mice
Open accessAbstract
Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Inflammatory monocytes-but not the noninflammatory subset-depend on the chemokine receptor CCR2 for localization to injured tissue. Here we present an optimized lipid nanoparticle and a CCR2-silencing short interfering RNA that, when administered systemically in mice, show rapid blood clearance, accumulate in spleen and bone marrow, and localize to monocytes. Efficient degradation of CCR2 mRNA in monocytes prevents their accumulation in sites of inflammation. Specifically, the treatment attenuates their number in atherosclerotic plaques, reduces infarct size after coronary artery occlusion, prolongs normoglycemia in diabetic mice after pancreatic islet transplantation, and results in reduced tumor volumes and lower numbers of tumor-associated macrophages.
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Liposome-dependent delivery of siRNA against CCR2 inhibited monocyte/macrophage recruitment to atherosclerotic lesion and arteries.
“Liposome-dependent delivery of siRNA against the chemokine receptor CCR2 also inhibited monocyte/macrophage recruitment to the atherosclerotic lesion and arteries.158”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [158]
Substantial degradation of CCR2 mRNA in monocytes inhibited their accumulation at inflammation site.
“Substantial degradation of CCR2mRNA in monocytes inhibited their accumulation at the inflammation site.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [158]
CCR2-silencing siRNA accumulated in spleen and bone marrow and localized to monocytes after systemic administration in mice.
“After systemic administration in mice, CCR2-silencing siRNA accumulated in the spleen and bone marrow and localized to monocytes.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [158]
CCR2 siRNA treatment reduced monocyte number in atherosclerotic plaques and reduced infarct size after coronary artery occlusion.
“Moreover, treatment reduced their number in atherosclerotic plaques and reduced the infarct size after coronary artery occlusion.158”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [158]
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References 45 · Cited by 839
- Authors
- Leuschner, F., Dutta, P., Gorbatov, R., Novobrantseva, T. I., Donahoe, J. S., Courties, G., Lee, K. M., Kim, J. I., Markmann, J. F., Marinelli, B., Panizzi, P., Lee, W. W., Iwamoto, Y., Milstein, S., Epstein-Barash, H., Cantley, W., Wong, J., Cortez-Retamozo, V., Newton, A., Love, K., Libby, P., Pittet, M. J., Swirski, F. K., Koteliansky, V., Langer, R., Weissleder, R., Anderson, D. G., & Nahrendorf, M.
- Affiliations
- Harvard University (US)
- Alnylam Pharmaceuticals (United States) (US)
- Massachusetts General Hospital (US)
- Auburn University (US)
- Seoul National University Bundang Hospital (KR)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Weissleder, Ralph
- Nahrendorf, Matthias
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2011-10-09
- Volume
- 29
- Issue
- 11
- Pages
- 1005-1010
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC3212614
- OpenAlex
- W2041663579
- Cited by
- 839
- References
- 45
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 47 · 2023: 53 · 2022: 60 · 2021: 66 · 2020: 71 · 2019: 58 · 2018: 44 · 2017: 73 · 2016: 60 · 2015: 59 · 2014: 63 · 2013: 59 · 2012: 57
- FWCI
- 24.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- Funders
- National Institutes of Health (4r37eb000244-34, 1r01ca132091-01)
- U.S. Public Health Service (268201000044C)
- National Heart, Lung, and Blood Institute (HHSN268201000044C, R01HL095629, R01HL096576, R01HL095612)
- National Cancer Institute (T32-CA 79443, P50-CA-86355, U24CA092782, P50CA086355, R01CA115527, R01-CA132091, T32CA079443, U24 CA92782)
- National Institute of Allergy and Infectious Diseases (R01AI084880, R01AI057851)
- National Institute of Biomedical Imaging and Bioengineering (R37-EB000244, R01EB006432)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- siRNA delivery, lipid nanoparticles, CCR2, inflammatory monocytes, targeted gene silencing, atherosclerosis, myocardial infarction, islet transplantation, diabetes mellitus, tumor-associated macrophages, graft rejection, inflammation
- MeSH terms
- Animals, Blood Glucose, Diabetes Mellitus, Disease Models, Animal, Graft Survival, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Monocytes, Myocardial Infarction, Islets of Langerhans Transplantation, Gene Silencing, RNA, Small Interfering, Atherosclerosis, Mice, Nanoparticles, Receptors, CCR2
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