Imidazole‐Based Synthetic Lipidoids for In Vivo mRNA Delivery into Primary T Lymphocytes

Engineering T lymphocytes is an emerging approach in a variety of biomedical applications. However, delivering large biologics to primary T lymphocytes directly in vivo is technically challenging due to the low transfection efficacy. Herein, we investigated a library of synthetic lipid‐like molecule...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2020-11, Vol.59 (45), p.20083-20089
Main Authors: Zhao, Xuewei, Chen, Jinjin, Qiu, Min, Li, Yamin, Glass, Zachary, Xu, Qiaobing
Format: Article
Language:English
Subjects:
Animals
Biomedical materials
combinatorial chemistry
Correlation analysis
drug delivery
gene therapy
Gene Transfer Techniques
HeLa Cells
Humans
Imidazole
imidazole-containing lipids
Imidazoles - chemistry
Intravenous administration
Libraries
Lipids
Lipids - chemistry
Lymphocytes
Lymphocytes T
Mice
mRNA
Recombination
RNA, Messenger - administration & dosage
T cell engineering
T-Lymphocytes - metabolism
Transfection
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Summary:Engineering T lymphocytes is an emerging approach in a variety of biomedical applications. However, delivering large biologics to primary T lymphocytes directly in vivo is technically challenging due to the low transfection efficacy. Herein, we investigated a library of synthetic lipid‐like molecules (lipidoids) for their capability of delivering mRNA into primary T lymphocytes both ex vivo and in vivo. We initially screened a library with a large structural variety of lipidoids ex vivo and identified imidazole‐containing lipidoids that are particularly potent in T lymphocytes transfection. We further optimized lipidoid structures by constructing and screening a detailed lipidoid library containing imidazole or imidazole analogues to perform a structure–activity correlation analysis. Using the lead lipidoid as a delivery vehicle for Cre mRNA in vivo through intravenous injection, we achieved 8.2 % gene recombination in mouse T lymphocytes. We used rough‐to‐detailed screening approaches to analyze the structure–activity relationship of T lymphocyte transfection. We identified new lipidoids containing imidazole for effective T lymphocyte transfection and in vivo gene recombination. Overall, our findings establish an improved non‐viral delivery platform of functional mRNA for the direct transfection of T lymphocytes in the body.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202008082