Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing
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 <i>in vivo</i> 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 <i>in vivo</i> 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.
Authors
- Daniel J. Siegwart (ORCID: https://orcid.org/0000-0003-3823-1931)
- Joshua Robinson (ORCID: https://orcid.org/0000-0002-6200-2904)
- Amogh Vaidya (ORCID: https://orcid.org/0000-0003-0712-659X)
- Jet Tsien (ORCID: https://orcid.org/0000-0002-2052-8051)
- Xiaoyan Bian (ORCID: https://orcid.org/0000-0002-6263-5269)
- Tian Qin (ORCID: https://orcid.org/0000-0001-7225-3224)
- Yun‐Chieh Sung (ORCID: https://orcid.org/0000-0001-7525-0694)
- Chao Hu (ORCID: https://orcid.org/0000-0003-3237-5934)
- Fangyu Zhang (ORCID: https://orcid.org/0000-0002-6522-5230)
- Shiying Wu (ORCID: https://orcid.org/0000-0002-6902-9544)
- Yehui Sun (ORCID: https://orcid.org/0000-0003-0215-6095)
- Yufen Xiao (ORCID: https://orcid.org/0000-0002-5604-7479)
- Pratima Basak
- Xizhen Lian
- Yangyang Yang (ORCID: https://orcid.org/0000-0002-6364-3340)
- Zeru Tian (ORCID: https://orcid.org/0000-0002-0437-2632)
- Erick Guerrero (ORCID: https://orcid.org/0000-0002-2076-3537)
- Xu Wang (ORCID: https://orcid.org/0000-0002-8925-5645)
- Minjeong Kim (ORCID: https://orcid.org/0000-0002-0524-9281)
- Zexiang Chen (ORCID: https://orcid.org/0000-0003-1791-9729)
Institutions
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-12-10
- DOI
- https://doi.org/10.1021/jacs.4c13154
- Citations
- 11
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- National Science Foundation
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- University of Texas Southwestern Medical Center
- National Institutes of Health
- National Cancer Institute
- National Institute of Biomedical Imaging and Bioengineering
- Division of Chemistry