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  3. Nature-inspired platform nanotechnology for RNA delivery to myeloid cells and their bone marrow progenitors

Nature-inspired platform nanotechnology for RNA delivery to myeloid cells and their bone marrow progenitors

  • Nat Nanotechnol. 2025 Apr;20(4):532-542. doi: 10.1038/s41565-024-01847-3.
Stijn R J Hofstraat # 1 2,  Tom Anbergen # 3,  Robby Zwolsman # 1 2,  Jeroen Deckers 3,  Yuri van Elsas 3,  Mirre M Trines 1 2,  Iris Versteeg 3,  Daniek Hoorn 1 2,  Gijs W B Ros 3,  Branca M Bartelet 3,  Merel M A Hendrikx 1 4,  Youssef B Darwish 1,  Teun Kleuskens 1,  Francisca Borges 3,  Rianne J F Maas 3,  Lars M Verhalle 1,  Willem Tielemans 3,  Pieter Vader 5,  Olivier G de Jong 6,  Tommaso Tabaglio 7,  Dave Keng Boon Wee 7,  Abraham J P Teunissen 8 9 10 11,  Eliane Brechbühl 8,  Henk M Janssen 12,  P Michel Fransen 12,  Anne de Dreu 1 2,  David P Schrijver 1 2,  Bram Priem 3,  Yohana C Toner 3,  Thijs J Beldman 3,  Mihai G Netea 3 13,  Willem J M Mulder 14 15 16,  Ewelina Kluza 1 2,  Roy van der Meel 17 18
Affiliations

Affiliations

  • 1 Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
  • 2 Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, the Netherlands.
  • 3 Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4 Biotrip B.V., Eindhoven, the Netherlands.
  • 5 CDL Research & Department of Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 6 Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands.
  • 7 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 8 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 9 Department of Diagnostic, Molecular, and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 10 Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 SyMO-Chem B.V., Eindhoven, the Netherlands.
  • 13 Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • 14 Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands. willem.mulder@radboudumc.nl.
  • 15 Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, the Netherlands. willem.mulder@radboudumc.nl.
  • 16 Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. willem.mulder@radboudumc.nl.
  • 17 Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands. r.v.d.meel@tue.nl.
  • 18 Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, the Netherlands. r.v.d.meel@tue.nl.
  • # Contributed equally.
PMID: 39900620 DOI: 10.1038/s41565-024-01847-3
Abstract

Nucleic acid therapeutics are used for silencing, expressing or editing genes in vivo. However, their systemic stability and targeted delivery to bone marrow resident cells remains a challenge. In this study we present a nanotechnology platform based on natural lipoproteins, designed for delivering small interfering RNA (siRNA), Antisense Oligonucleotides and messenger RNA to myeloid cells and haematopoietic stem and progenitor cells in the bone marrow. We developed a prototype Apolipoprotein nanoparticle (aNP) that stably incorporates siRNA into its core. We then created a comprehensive library of aNP formulations and extensively characterized their physicochemical properties and in vitro performance. From this library, we selected eight representative aNP-siRNA formulations and evaluated their ability to silence lysosomal-associated membrane protein 1 (Lamp1) expression in immune cell subsets in mice after intravenous administration. Using the most effective aNP identified from the screening process, we tested the platform's potential for therapeutic gene silencing in a syngeneic murine tumour model. We also demonstrated the aNP platform's suitability for splice-switching with Antisense Oligonucleotides and for protein production with messenger RNA by myeloid progenitor cells in the bone marrow. Our data indicate that the aNP platform holds translational potential for delivering various types of nucleic acid therapeutics to myeloid cells and their progenitors.

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