Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo

  • Nidhi Jyotsana
  • Amit Sharma
  • Anuhar Chaturvedi
  • Ramachandramouli Budida
  • Michaela Scherr
  • Florian Kuchenbauer
  • Robert Lindner
  • Fatih Noyan
  • Kurt-Wolfram Sühs
  • Martin Stangel
  • Denis Grote-Koska
  • Korbinian Brand
  • Hans-Peter Vornlocher
  • Matthias Eder
  • Felicitas Thol
  • Arnold Ganser
  • R. Keith Humphries
  • Euan Ramsay
  • Pieter Cullis
  • Michael HeuserEmail author
Original Article


Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.


Lipid nanoparticle BCR-ABL RNAi Chronic myeloid leukemia 



We thank Silke Glowotz, Martin Wichmann, Anitha Thomas and Colin Walsh for technical support. We express sincere thanks to the patients for their participation in the study. We thank Prof. Dr. Alf Lamprecht and Dr. Manusmriti Singh for providing us nanoparticles during the initial experiments. We thank the staff of the Central Animal Facility and Matthias Ballmaier from the Cell Sorting Core Facility (supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft) of Hannover Medical School.

Authors’ contributions

N.J. and M.H. designed the research; N.J., A.S., A.C., M.S., R.B., M.S., F.K., R.L., F.N., K.W. S., M.S., D.G.K., K.B., H.P.V., M.E., A.G., F.T., R.K.H., E.R., P.C., and M.H. performed the research; N.J., A.S., and M.H. analyzed the data. N.J. and M.H. wrote the manuscript. All authors read and agreed to the final version of the manuscript.

Funding information

This study was supported by the Rudolf-Bartling Stiftung, an ERC grant under the European Union’s Horizon 2020 research and innovation program (No. 638035), grant 111,267 from Deutsche Krebshilfe, DFG grant HE 5240/5-2 and HE 5240/6-2; grants from Dieter-Schlag Stiftung and a Terry Fox Foundation Program Project Award to RKH.

Compliance with ethical standards

Conflict of interest

Euan Ramsay is an employee of Precision Nanosystems. Pieter Cullis is founder of Precision Nanosystems. The other authors have no conflicts of interest.

Supplementary material

277_2019_3713_MOESM1_ESM.docx (3.9 mb)
ESM 1 (DOCX 3987 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Nidhi Jyotsana
    • 1
  • Amit Sharma
    • 1
  • Anuhar Chaturvedi
    • 1
  • Ramachandramouli Budida
    • 2
  • Michaela Scherr
    • 1
  • Florian Kuchenbauer
    • 3
  • Robert Lindner
    • 4
  • Fatih Noyan
    • 5
  • Kurt-Wolfram Sühs
    • 6
  • Martin Stangel
    • 6
  • Denis Grote-Koska
    • 7
  • Korbinian Brand
    • 7
  • Hans-Peter Vornlocher
    • 8
  • Matthias Eder
    • 1
  • Felicitas Thol
    • 1
  • Arnold Ganser
    • 1
  • R. Keith Humphries
    • 9
    • 10
  • Euan Ramsay
    • 11
  • Pieter Cullis
    • 12
  • Michael Heuser
    • 1
    Email author
  1. 1.Department of Hematology, Hemostasis, Oncology and Stem Cell TransplantationHannover Medical SchoolHannoverGermany
  2. 2.Department of Immunology and RheumatologyHannover Medical SchoolHannoverGermany
  3. 3.Department of Internal Medicine IIIUniversity Hospital of UlmUlmGermany
  4. 4.Department of Cell Biology, Center of AnatomyHannover Medical SchoolHannoverGermany
  5. 5.Department of Gastroenterology, Hepatology & EndocrinologyHannover Medical SchoolHannoverGermany
  6. 6.Clinic for NeurologyHannover Medical SchoolHannoverGermany
  7. 7.Department of Clinical ChemistryHannover Medical SchoolHannoverGermany
  8. 8.Axolabs GmBHKulmbachGermany
  9. 9.Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverCanada
  10. 10.Department of MedicineUniversity of British ColumbiaVancouverCanada
  11. 11.Precision NanoSystems IncVancouverCanada
  12. 12.Department of Biochemistry and Molecular BiologyUniversity of British ColumbiaVancouverCanada

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