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The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs

The regulatory approval of Onpattro, a lipid nanoparticle-based short interfering RNA drug for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis, paves the way for clinical development of many nucleic acid-based therapies enabled by nanoparticle delivery.

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Fig. 1: Integrated model of lipid nanoparticle (LNP)-mediated delivery of siRNA to hepatocytes in vivo.
Fig. 2: LNP siRNA systems containing 2nd generation ionizable aminolipids exhibit greatly improved potency for silencing factor VII (FVII) in the liver.
Fig. 3: Phase I clinical trials of ALN-TTR01 and ALN-TTR02 (patisiran).


  1. 1.

    Allen, T. M. & Cullis, P. R. Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65, 36–48 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Cullis, P. R., Mayer, L. D., Bally, M. B., Madden, T. D. & Hope, M. J. Generating and loading of liposomal systems for drug-delivery applications. Adv. Drug Deliv. Rev. 3, 267–282 (1989).

    CAS  Article  Google Scholar 

  3. 3.

    Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Semple, S. C. et al. Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures. Biochim. Biophys. Acta Biomembr. 1510, 152–166 (2001).

    CAS  Article  Google Scholar 

  5. 5.

    Kulkarni, J. A. et al. On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA. ACS Nano 12, 4787–4795 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Belliveau, N. M. et al. Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Mol. Ther. Nucleic Acids 1, e37 (2012).

    Article  Google Scholar 

  7. 7.

    Mui, B. L. et al. Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol. Ther. Nucleic Acids 2, e139 (2013).

    CAS  Article  Google Scholar 

  8. 8.

    Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).

    CAS  Article  Google Scholar 

  9. 9.

    Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).

    CAS  Article  Google Scholar 

  10. 10.

    Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. 51, 8529–8533 (2012).

    CAS  Article  Google Scholar 

  11. 11.

    Hafez, I. M., Maurer, N. & Cullis, P. R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).

    CAS  Article  Google Scholar 

  12. 12.

    Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    CAS  Article  Google Scholar 

  13. 13.

    Coelho, T. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819–829 (2013).

    CAS  Article  Google Scholar 

  14. 14.

    Leung, A. K. K., Tam, Y. Y. C., Chen, S., Hafez, I. M. & Cullis, P. R. Microfluidic mixing: a general method for encapsulating macromolecules in lipid nanoparticle systems. J. Phys. Chem. B 119, 8698–8706 (2015).

    CAS  Article  Google Scholar 

  15. 15.

    Kulkarni, J. A. et al. Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads. Nanoscale 11, 9023–9031 (2019).

    CAS  Article  Google Scholar 

  16. 16.

    Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217, 345–351 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Pardi, N. et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat. Commun. 8, 14630 (2017).

    Article  Google Scholar 

  18. 18.

    Thess, A. et al. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol. Ther. 23, 1456–1464 (2015).

    CAS  Article  Google Scholar 

  19. 19.

    Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017).

    CAS  Article  Google Scholar 

  20. 20.

    Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018).

    Article  Google Scholar 

  21. 21.

    Finn, J. D. et al. A S single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 22, 2227–2235 (2018).

    CAS  Article  Google Scholar 

  22. 22.

    Conway, A. et al. Non-viral delivery of zinc finger nuclease mrna enables highly efficient in vivo genome editing of multiple therapeutic gene targets. Mol. Ther. 27, 866–877 (2019).

    CAS  Article  Google Scholar 

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Correspondence to Pieter R. Cullis.

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Competing interests

A.A., M.A.M., M.M., K.F., M.J. and S.B. are employees of Alnylam Pharmaceuticals. S.A., X.D., M.J.H., T.D.M., B.L.M., S.C.S. and Y.K.T. are employees of Acuitas. P.R.C. has financial holdings in Acuitas.

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Akinc, A., Maier, M.A., Manoharan, M. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019).

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