Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism

Zhijian Li, Laura Amaya, Ruoxi Pi, Sean K. Wang, Alok Ranjan, Robert M. Waymouth, Catherine A. Blish, Howard Y. Chang and Paul A. Wender ()
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Zhijian Li: Stanford University
Laura Amaya: Stanford University
Ruoxi Pi: Department of Medicine
Sean K. Wang: Stanford University
Alok Ranjan: Stanford University
Robert M. Waymouth: Stanford University
Catherine A. Blish: Department of Medicine
Howard Y. Chang: Stanford University
Paul A. Wender: Stanford University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The introduction of more effective and selective mRNA delivery systems is required for the advancement of many emerging biomedical technologies including the development of prophylactic and therapeutic vaccines, immunotherapies for cancer and strategies for genome editing. While polymers and oligomers have served as promising mRNA delivery systems, their efficacy in hard-to-transfect cells such as primary T lymphocytes is often limited as is their cell and organ tropism. To address these problems, considerable attention has been placed on structural screening of various lipid and cation components of mRNA delivery systems. Here, we disclose a class of charge-altering releasable transporters (CARTs) that differ from previous CARTs based on their beta-amido carbonate backbone (bAC) and side chain spacing. These bAC-CARTs exhibit enhanced mRNA transfection in primary T lymphocytes in vitro and enhanced protein expression in vivo with highly selective spleen tropism, supporting their broader therapeutic use as effective polyanionic delivery systems.

Date: 2023
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DOI: 10.1038/s41467-023-42672-x

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