Dendrimers Improve Apolipoprotein Nanoparticle mRNA Delivery to Immune Cells
Abstract
Abstract Employing messenger RNA (mRNA) for protein production in the liver or for vaccine purposes is a promising therapeutic approach. However, unlocking mRNA's full therapeutic potential requires systemic delivery platform technology with controllable biodistribution features. Apolipoprotein nanoparticles (aNP) containing monovalent ionizable cationic lipids have been shown to functionally deliver mRNA to myeloid progenitor cells in the bone marrow after intravenous administration. Here, the development of polyvalent ionizable cationic dendrimers is reported for incorporation in aNPs to enable efficient mRNA complexation and functional delivery. A library of dendrimers is first rationally designed with diverse hydrophobic core units, a number of branching units, and functionalized terminal units. Upon incorporation, eleven distinct dendrimer‐based aNP‐mRNA formulations are screened and characterized in vitro for their properties. Based on the screening outcome, four formulations are selected and evaluated their ability to induce functional gene expression in vivo. The results indicate that the lead polyvalent dendrimer‐based aNP formulation outperformed formulations containing a clinically approved ionizable cationic lipid regarding gene expression in hematopoietic stem and progenitor cells in the bone marrow after intravenous administration.
Article Details
Authors (25)
Mirre M. Trines
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Daniek Hoorn
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Stijn R.J. Hofstraat
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Robby C. Zwolsman
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Tom Anbergen
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Iris Versteeg
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Yuri van Elsas
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Jeroen Deckers
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Merel M.A. Hendrikx
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Teun Kleuskens
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Youssef B. Darwish
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Gijs W.B. Ros
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Sjoerd F. Dijkstra
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Bram Priem
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Matt Timmers
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
P. Michel Fransen
SyMO‐Chem B.V. Eindhoven 5612 AZ The Netherlands
Maarten J. Pouderoijen
SyMO‐Chem B.V. Eindhoven 5612 AZ The Netherlands
Bas F.M. de Waal
Laboratory of Macromolecular and Organic Chemistry Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
E.W. Meijer
Laboratory of Macromolecular and Organic Chemistry Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Thijs J. Beldman
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Yohana C. Toner
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen 6525 GA The Netherlands
Ewelina Kluza
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Willem J.M. Mulder
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands
Henk M. Janssen
SyMO‐Chem B.V. Eindhoven 5612 AZ The Netherlands
Roy van der Meel
Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Eindhoven 5600 MB The Netherlands