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<p>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 (<i>Lamp1</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月3日

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  • Stijn R. J. Hofstraat,
  • Tom Anbergen,
  • Robby Zwolsman,
  • Jeroen Deckers,
  • Yuri van Elsas,
  • Mirre M. Trines,
  • Iris Versteeg,
  • Daniek Hoorn,
  • Gijs W. B. Ros,
  • Branca M. Bartelet,
  • Merel M. A. Hendrikx,
  • Youssef B. Darwish,
  • Teun Kleuskens,
  • Francisca Borges,
  • Rianne J. F. Maas,
  • Lars M. Verhalle,
  • Willem Tielemans,
  • Pieter Vader,
  • Olivier G. de Jong,
  • Tommaso Tabaglio,
  • Dave Keng Boon Wee,
  • Abraham J. P. Teunissen,
  • Eliane Brechbühl,
  • Henk M. Janssen,
  • P. Michel Fransen,
  • Anne de Dreu,
  • David P. Schrijver,
  • Bram Priem,
  • Yohana C. Toner,
  • Thijs J. Beldman,
  • Mihai G. Netea,
  • Willem J. M. Mulder,
  • Ewelina Kluza,
  • Roy van der Meel

摘要

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.