Nature-inspired platform nanotechnology for RNA delivery to myeloid cells and their bone marrow progenitors
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.
Authors
- Jeroen Deckers (ORCID: https://orcid.org/0000-0003-2723-8660)
- Thijs J. Beldman (ORCID: https://orcid.org/0000-0003-4742-636X)
- Eliane E.S. Brechbühl (ORCID: https://orcid.org/0000-0003-1386-4601)
- Y. Darwish (ORCID: https://orcid.org/0000-0003-2035-7579)
- Mihai Gheorghe Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
- Mirre M. Trines
- David P. Schrijver
- Tommaso Tabaglio (ORCID: https://orcid.org/0000-0001-6873-3073)
- Willem J. M. Mulder (ORCID: https://orcid.org/0000-0001-8665-3878)
- Ewelina Kluza (ORCID: https://orcid.org/0000-0002-7040-0427)
- Roy van der Meel (ORCID: https://orcid.org/0000-0002-2200-7946)
- Tom Anbergen (ORCID: https://orcid.org/0000-0002-7155-7709)
- Yuri van Elsas (ORCID: https://orcid.org/0009-0002-2985-3368)
- Gloria Ros (ORCID: https://orcid.org/0000-0003-2214-5254)
- Anne de Dreu (ORCID: https://orcid.org/0000-0001-6538-009X)
- Yohana Camila Antunes Frederico
- Stijn R. J. Hofstraat (ORCID: https://orcid.org/0000-0003-2120-5171)
- Abraham J. P. Teunissen (ORCID: https://orcid.org/0000-0002-0401-8262)
- Pieter Vader
- Henk M. Janssen (ORCID: https://orcid.org/0000-0002-2588-846X)
- Bram Priem (ORCID: https://orcid.org/0009-0002-6793-816X)
- Olivier G. de Jong (ORCID: https://orcid.org/0000-0002-5952-9617)
- Robby Zwolsman (ORCID: https://orcid.org/0000-0001-6059-2982)
- Teun Kleuskens
- Lars M. Verhalle
- Willem Tielemans (ORCID: https://orcid.org/0009-0004-2670-509X)
- Daniek Hoorn
- Francisca Borges (ORCID: https://orcid.org/0000-0002-6564-8516)
- M. Hendrikx (ORCID: https://orcid.org/0009-0000-3553-5927)
- Rianne Maas (ORCID: https://orcid.org/0000-0003-1521-3116)
- Peter Fransen (ORCID: https://orcid.org/0000-0002-7239-7225)
- Dave Keng Boon Wee
- Iris Versteeg
- Branca M. Bartelet
Institutions
- NXP (Netherlands) (NL)
- Agency for Science, Technology and Research (SG)
- University of Bonn (DE)
- Radboud University Nijmegen (NL)
- Utrecht University (NL)
- Radboud University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- SyMO-Chem (Netherlands) (NL)
- Institute of Molecular and Cell Biology (SG)
- Eindhoven University of Technology (NL)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Nanotechnology
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1038/s41565-024-01847-3
- Citations
- 37
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 29.82
Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek