A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

S.R.J. Hofstraat; T. Anbergen; Robby Zwolsman; Jeroen Deckers; Yuri van Elsas; Mirre M. Trines; Iris Versteeg; Bram Priem; Youssef B. Darwish; T.M.A. Kleuskens; Francisca Borges; Rianne Maas; Lars Verhalle; Willem Tielemans; Pieter Vader; Olivier de Jong; Abraham J.P. Teunissen; Eliane Brechbühl; Henk M. Janssen; Pieter Michele Fransen; Anne de Dreu; David P. Schrijver; Yohana C. Toner; Thijs J. Beldman; Mihai Netea; Willem J.M. Mulder; Ewelina Kluza; Roy van der Meel

doi:10.21203/rs.3.rs-3458536/v1

A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

S.R.J. Hofstraat, T. Anbergen, Robby Zwolsman, Jeroen Deckers, Yuri van Elsas, Mirre M. Trines, Iris Versteeg, Bram Priem, Youssef B. Darwish, T.M.A. Kleuskens, Francisca Borges, Rianne Maas, Lars Verhalle, Willem Tielemans, Pieter Vader, Olivier de Jong, Abraham J.P. Teunissen, Eliane Brechbühl, Henk M. Janssen, Pieter Michele FransenAnne de Dreu, David P. Schrijver, Yohana C. Toner, Thijs J. Beldman, Mihai Netea, Willem J.M. Mulder, Ewelina Kluza, Roy van der Meel

Research output: Working paper › Preprint › Academic

Abstract

Nucleic acid therapeutics harbor great potential for silencing, expressing, or editing genes. Here, we introduce a nanodelivery platform based on natural lipoproteins, which prevents premature degradation of small interfering RNA (siRNA), ensuring its targeted and intracellular delivery to hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. After establishing a prototype apolipoprotein lipid nanoparticle (aNP) that stably incorporates siRNA in its core, we built a comprehensive library of which we thoroughly characterized the individual aNPs’ physicochemical properties. Following the in vitro screening of all formulations, we selected eight siRNA-aNPs that are representative of the library’s diversity, and determined their capacity to silence lysosomal-associated membrane protein 1 (LAMP1) in immune cell subsets in mice, using an intravenous administration regimen. Our data show that using different aNPs, we can achieve functional gene silencing in immune cell subsets and their bone marrow progenitors. Beyond gene silencing, the aNP platform’s inherent capacity to engage immune cells provides it with considerable potential to deliver other types of nucleic acid therapeutics to HSPCs.

Original language	English
Publisher	Research Square
DOIs	https://doi.org/10.21203/rs.3.rs-3458536/v1
Publication status	Published - 27 Oct 2023

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Hofstraat, S. R. J., Anbergen, T., Zwolsman, R., Deckers, J., van Elsas, Y., Trines, M. M., Versteeg, I., Priem, B., B. Darwish, Y., Kleuskens, T. M. A., Borges, F., Maas, R., Verhalle, L., Tielemans, W., Vader, P., de Jong, O., Teunissen, A. J. P., Brechbühl, E., Janssen, H. M., ... van der Meel, R. (2023). A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells. Research Square. https://doi.org/10.21203/rs.3.rs-3458536/v1

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title = "A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells",

abstract = "Nucleic acid therapeutics harbor great potential for silencing, expressing, or editing genes. Here, we introduce a nanodelivery platform based on natural lipoproteins, which prevents premature degradation of small interfering RNA (siRNA), ensuring its targeted and intracellular delivery to hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. After establishing a prototype apolipoprotein lipid nanoparticle (aNP) that stably incorporates siRNA in its core, we built a comprehensive library of which we thoroughly characterized the individual aNPs{\textquoteright} physicochemical properties. Following the in vitro screening of all formulations, we selected eight siRNA-aNPs that are representative of the library{\textquoteright}s diversity, and determined their capacity to silence lysosomal-associated membrane protein 1 (LAMP1) in immune cell subsets in mice, using an intravenous administration regimen. Our data show that using different aNPs, we can achieve functional gene silencing in immune cell subsets and their bone marrow progenitors. Beyond gene silencing, the aNP platform{\textquoteright}s inherent capacity to engage immune cells provides it with considerable potential to deliver other types of nucleic acid therapeutics to HSPCs.",

author = "S.R.J. Hofstraat and T. Anbergen and Robby Zwolsman and Jeroen Deckers and {van Elsas}, Yuri and Trines, {Mirre M.} and Iris Versteeg and Bram Priem and {B. Darwish}, Youssef and T.M.A. Kleuskens and Francisca Borges and Rianne Maas and Lars Verhalle and Willem Tielemans and Pieter Vader and {de Jong}, Olivier and Teunissen, {Abraham J.P.} and Eliane Brechb{\"u}hl and Janssen, {Henk M.} and Fransen, {Pieter Michele} and {de Dreu}, Anne and Schrijver, {David P.} and Toner, {Yohana C.} and Beldman, {Thijs J.} and Mihai Netea and Mulder, {Willem J.M.} and Ewelina Kluza and {van der Meel}, Roy",

year = "2023",

month = oct,

day = "27",

doi = "10.21203/rs.3.rs-3458536/v1",

language = "English",

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Hofstraat, SRJ, Anbergen, T, Zwolsman, R, Deckers, J, van Elsas, Y, Trines, MM, Versteeg, I, Priem, B, B. Darwish, Y, Kleuskens, TMA, Borges, F, Maas, R, Verhalle, L, Tielemans, W, Vader, P, de Jong, O, Teunissen, AJP, Brechbühl, E, Janssen, HM, Fransen, PM, de Dreu, A , Schrijver, DP, Toner, YC, Beldman, TJ, Netea, M , Mulder, WJM , Kluza, E & van der Meel, R 2023 'A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells' Research Square. https://doi.org/10.21203/rs.3.rs-3458536/v1

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T1 - A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

AU - Hofstraat, S.R.J.

AU - Anbergen, T.

AU - Zwolsman, Robby

AU - Deckers, Jeroen

AU - van Elsas, Yuri

AU - Trines, Mirre M.

AU - Versteeg, Iris

AU - Priem, Bram

AU - B. Darwish, Youssef

AU - Kleuskens, T.M.A.

AU - Borges, Francisca

AU - Maas, Rianne

AU - Verhalle, Lars

AU - Tielemans, Willem

AU - Vader, Pieter

AU - de Jong, Olivier

AU - Teunissen, Abraham J.P.

AU - Brechbühl, Eliane

AU - Janssen, Henk M.

AU - Fransen, Pieter Michele

AU - de Dreu, Anne

AU - Schrijver, David P.

AU - Toner, Yohana C.

AU - Beldman, Thijs J.

AU - Netea, Mihai

AU - Mulder, Willem J.M.

AU - Kluza, Ewelina

AU - van der Meel, Roy

PY - 2023/10/27

Y1 - 2023/10/27

N2 - Nucleic acid therapeutics harbor great potential for silencing, expressing, or editing genes. Here, we introduce a nanodelivery platform based on natural lipoproteins, which prevents premature degradation of small interfering RNA (siRNA), ensuring its targeted and intracellular delivery to hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. After establishing a prototype apolipoprotein lipid nanoparticle (aNP) that stably incorporates siRNA in its core, we built a comprehensive library of which we thoroughly characterized the individual aNPs’ physicochemical properties. Following the in vitro screening of all formulations, we selected eight siRNA-aNPs that are representative of the library’s diversity, and determined their capacity to silence lysosomal-associated membrane protein 1 (LAMP1) in immune cell subsets in mice, using an intravenous administration regimen. Our data show that using different aNPs, we can achieve functional gene silencing in immune cell subsets and their bone marrow progenitors. Beyond gene silencing, the aNP platform’s inherent capacity to engage immune cells provides it with considerable potential to deliver other types of nucleic acid therapeutics to HSPCs.

AB - Nucleic acid therapeutics harbor great potential for silencing, expressing, or editing genes. Here, we introduce a nanodelivery platform based on natural lipoproteins, which prevents premature degradation of small interfering RNA (siRNA), ensuring its targeted and intracellular delivery to hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. After establishing a prototype apolipoprotein lipid nanoparticle (aNP) that stably incorporates siRNA in its core, we built a comprehensive library of which we thoroughly characterized the individual aNPs’ physicochemical properties. Following the in vitro screening of all formulations, we selected eight siRNA-aNPs that are representative of the library’s diversity, and determined their capacity to silence lysosomal-associated membrane protein 1 (LAMP1) in immune cell subsets in mice, using an intravenous administration regimen. Our data show that using different aNPs, we can achieve functional gene silencing in immune cell subsets and their bone marrow progenitors. Beyond gene silencing, the aNP platform’s inherent capacity to engage immune cells provides it with considerable potential to deliver other types of nucleic acid therapeutics to HSPCs.

U2 - 10.21203/rs.3.rs-3458536/v1

DO - 10.21203/rs.3.rs-3458536/v1

M3 - Preprint

BT - A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

PB - Research Square

ER -

A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

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