Abstract

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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Acknowledgements

The authors thank M. Waring, A. Chicoine and the Ragon Institute (MGH) for cell sorting, the CSB Mouse Imaging Program (P. Waterman, B. Sena) and B. Bettencourt for designing initial sets of siRNA. We acknowledge the small, medium and large scale RNA synthesis groups at Alnylam as well as analytical, duplex annealing and QC groups for synthesizing and characterizing RNAs. This work was funded in part by grants from the US National Institutes of Health R01-HL096576, R01-HL095629 (M.N.); R01-EB006432, T32-CA79443, U24-CA92782, P50-CA86355, HHSN268201000044C (R.W.); R01-CA132091, R01-CA115527, R37-EB000244 (R.L.); Deutsche Herzstiftung (F.L.); and the SNUBH Research Fund 02-2007-013 (W.W.L.).

Author information

Author notes

    • Florian Leuschner
    •  & Partha Dutta

    These authors contributed equally to this work.

Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Florian Leuschner
    • , Partha Dutta
    • , Rostic Gorbatov
    • , Jessica S Donahoe
    • , Gabriel Courties
    • , Brett Marinelli
    • , Yoshiko Iwamoto
    • , Virna Cortez-Retamozo
    • , Andita Newton
    • , Mikael J Pittet
    • , Filip K Swirski
    • , Ralph Weissleder
    •  & Matthias Nahrendorf
  2. Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

    • Tatiana I Novobrantseva
    • , Stuart Milstein
    • , Hila Epstein-Barash
    • , William Cantley
    • , Jamie Wong
    •  & Victor Koteliansky
  3. Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Kang Mi Lee
    • , James I Kim
    •  & James F Markmann
  4. Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.

    • Peter Panizzi
  5. Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul, Korea.

    • Won Woo Lee
  6. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Kevin Love
    • , Robert Langer
    •  & Daniel G Anderson
  7. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Peter Libby
  8. Department of Chemical Engineering, MIT, Cambridge, Massachusetts, USA.

    • Robert Langer
    •  & Daniel G Anderson
  9. Division of Health Science Technology, MIT, Cambridge, Massachusetts, USA.

    • Robert Langer
    •  & Daniel G Anderson
  10. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Ralph Weissleder

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Contributions

F.L. and P.D. performed experiments, collected and analyzed the data and contributed to writing the manuscript, R.G. did surgeries and performed experiments, T.I.N. designed experiments and siRNA screens, analyzed data and contributed to writing the manuscript; K.M.L. did islet transplantations and analyzed data, J.S.D., G.C., J.I.K., J.F.M., B.M., P.P., W.W.L., Y.I., V.C.-R., A.N., W.C., J.W. performed experiments, imaging, collected, analyzed and discussed data, S.M., H.E.-B., K.L. formulated siRNA nanoparticles, P.L., M.J.P. and F.K.S. conceived experiments and discussed strategy and results; V.K., R.L., R.W., D.G.A. and M.N. designed experiments, developed siRNA delivery technology and in vivo imaging strategies and systems, and reviewed, analyzed and discussed data. M.N. and R.W. wrote the manuscript which was edited and approved by all co-authors. M.N. developed and supervised the project.

Competing interests

T.I.N., S.M., H.E.B., W.C., J.W. and V.K. are Alnylam Pharmaceuticals employees; K.L., R.L., and D.G.A. receive funding from Alnylam Pharmaceuticals. R.L. and D.G.A. are consultants with Alnylam.

Corresponding authors

Correspondence to Ralph Weissleder or Matthias Nahrendorf.

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DOI

https://doi.org/10.1038/nbt.1989

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