TY - JOUR
T1 - Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing
AU - Wu, Shiying
AU - Yang, Yangyang
AU - Lian, Xizhen
AU - Zhang, Fangyu
AU - Hu, Chao
AU - Tsien, Jet
AU - Chen, Zexiang
AU - Sun, Yehui
AU - Vaidya, Amogh
AU - Kim, Minjeong
AU - Sung, Yun Chieh
AU - Xiao, Yufen
AU - Bian, Xiaoyan
AU - Wang, Xu
AU - Tian, Zeru
AU - Guerrero, Erick
AU - Robinson, Joshua
AU - Basak, Pratima
AU - Qin, Tian
AU - Siegwart, Daniel J.
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/12/18
Y1 - 2024/12/18
N2 - Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.1.1]pentane (BCP) core motifs. BCP-based lipids enabled efficient in vivo mRNA delivery to the liver and spleen with significantly greater performance over 2D benzene- and cyclohexane-based analogues. Notably, lead BCP-NC2-C12 LNPs mediated ∼90% reduction in the PCSK9 serum protein level via CRISPR/Cas9 gene knockout, outperforming 2D controls and clinically used DLin-MC3-DMA LNPs at the same dose. Here, we introduce BCP-based designs with superior in vivo activity, thereby expanding the chemical scope of ionizable amino lipids from 2D to 3D and offering a promising avenue to improve mRNA and gene editing efficiency for the continued development of genetic medicines.
AB - Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.1.1]pentane (BCP) core motifs. BCP-based lipids enabled efficient in vivo mRNA delivery to the liver and spleen with significantly greater performance over 2D benzene- and cyclohexane-based analogues. Notably, lead BCP-NC2-C12 LNPs mediated ∼90% reduction in the PCSK9 serum protein level via CRISPR/Cas9 gene knockout, outperforming 2D controls and clinically used DLin-MC3-DMA LNPs at the same dose. Here, we introduce BCP-based designs with superior in vivo activity, thereby expanding the chemical scope of ionizable amino lipids from 2D to 3D and offering a promising avenue to improve mRNA and gene editing efficiency for the continued development of genetic medicines.
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U2 - 10.1021/jacs.4c13154
DO - 10.1021/jacs.4c13154
M3 - Article
C2 - 39655603
AN - SCOPUS:85212575770
SN - 0002-7863
VL - 146
SP - 34733
EP - 34742
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 50
ER -
