TY - JOUR
T1 - A Combinatorial Library of Lipid Nanoparticles for Cell Type-Specific mRNA Delivery
AU - Naidu, Gonna Somu
AU - Yong, Seok Beom
AU - Ramishetti, Srinivas
AU - Rampado, Riccardo
AU - Sharma, Preeti
AU - Ezra, Assaf
AU - Goldsmith, Meir
AU - Hazan-Halevy, Inbal
AU - Chatterjee, Sushmita
AU - Aitha, Anjaiah
AU - Peer, Dan
N1 - Funding Information:
G.S.N. and S.-B.Y. contributed equally to this work. This work was partly supported by grants from the Dotan Center for hematological malignancies at Tel Aviv University and by the Shmunis Family Foundation awarded to D.P. S-B.Y. thanks the National Research Foundation of Korea for a Postdoctoral Fellowship (2021R1A6A3A03039300). All animal protocols were approved by the Tel Aviv University, Institutional Animal Care and Usage Committee and in accordance with current regulations and standards of the Israel Ministry of Health.
Funding Information:
G.S.N. and S.‐B.Y. contributed equally to this work. This work was partly supported by grants from the Dotan Center for hematological malignancies at Tel Aviv University and by the Shmunis Family Foundation awarded to D.P. S‐B.Y. thanks the National Research Foundation of Korea for a Postdoctoral Fellowship (2021R1A6A3A03039300). All animal protocols were approved by the Tel Aviv University, Institutional Animal Care and Usage Committee and in accordance with current regulations and standards of the Israel Ministry of Health.
Publisher Copyright:
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2023/7/6
Y1 - 2023/7/6
N2 - Ionizable lipid-based nanoparticles (LNPs) are the most advanced non-viral drug delivery systems for RNA therapeutics and vaccines. However, cell type-specific, extrahepatic mRNA delivery is still a major hurdle, hampering the development of novel therapeutic modalities. Herein, a novel ionizable lipid library is synthesized by modifying hydrophobic tail chains and linkers. Combined with other helper lipids and utilizing a microfluidic mixing approach, stable LNPs are formed. Using Luciferase-mRNA, mCherry mRNA, and Cre mRNA together with a TdTomato animal model, superior lipids forming LNPs for potent cell-type specific mRNA delivery are identified. In vitro assays concluded that combining branched ester tail chains with hydroxylamine linker negatively affects mRNA delivery efficiency. In vivo studies identify Lipid 23 as a liver-trophic, superior mRNA delivery lipid and Lipid 16 as a potent cell type-specific ionizable lipid for the CD11bhi macrophage population without an additional targeting moiety. Finally, in vivo mRNA delivery efficiency and toxicity of these LNPs are compared with SM-102-based LNP (Moderna's LNP formulation) and are shown to be cell-specific compared to SM-102-based LNPs. Overall, this study suggests that a structural combination of tail and linker can drive a novel functionality of LNPs in vivo.
AB - Ionizable lipid-based nanoparticles (LNPs) are the most advanced non-viral drug delivery systems for RNA therapeutics and vaccines. However, cell type-specific, extrahepatic mRNA delivery is still a major hurdle, hampering the development of novel therapeutic modalities. Herein, a novel ionizable lipid library is synthesized by modifying hydrophobic tail chains and linkers. Combined with other helper lipids and utilizing a microfluidic mixing approach, stable LNPs are formed. Using Luciferase-mRNA, mCherry mRNA, and Cre mRNA together with a TdTomato animal model, superior lipids forming LNPs for potent cell-type specific mRNA delivery are identified. In vitro assays concluded that combining branched ester tail chains with hydroxylamine linker negatively affects mRNA delivery efficiency. In vivo studies identify Lipid 23 as a liver-trophic, superior mRNA delivery lipid and Lipid 16 as a potent cell type-specific ionizable lipid for the CD11bhi macrophage population without an additional targeting moiety. Finally, in vivo mRNA delivery efficiency and toxicity of these LNPs are compared with SM-102-based LNP (Moderna's LNP formulation) and are shown to be cell-specific compared to SM-102-based LNPs. Overall, this study suggests that a structural combination of tail and linker can drive a novel functionality of LNPs in vivo.
KW - Combinatorial lipid nanoparticle
KW - Lipid nanoparticle
KW - cell type-specific mRNA delivery
KW - mRNA delivery
KW - Animals
KW - Nanoparticles/chemistry
KW - Lipids/chemistry
KW - RNA, Messenger/genetics
KW - combinatorial lipid nanoparticles
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U2 - 10.1002/advs.202301929
DO - 10.1002/advs.202301929
M3 - Article
C2 - 37092557
AN - SCOPUS:85153492586
SN - 2198-3844
VL - 10
SP - e2301929
JO - Advanced Science
JF - Advanced Science
IS - 19
M1 - 2301929
ER -