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Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters [Chemistry]

The transfection of lymphocytes with genetic material is a significant unmet need in immunotherapy and the treatment of many diseases. Current transfection strategies primarily rely on physical methods that must be conducted ex vivo and are often inefficient. We identified mixtures of lipid-varied mRNA delivery vehicles (charge-altering releasable transporters, CARTs) that show enhanced uptake into multiple lymphocyte cell types. The top performing lipid mixtures were rapidly identified using a combinatorial strategy and the resulting information was used to design single-delivery agents incorporating both lipid domains using our two-step organocatalytic ring-opening polymerization. Hybrid-lipid CARTs show >80% mRNA transfection efficiency in vitro and >1.5% lymphocyte transfection efficiency in mice, which is higher than previously reported systems. These materials should enable new immunotherapy strategies and applications.

Authors:   Colin J. McKinlay; Nancy L. Benner; Ole A. Haabeth; Robert M. Waymouth; Paul A. Wender
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   26
Year:   2018
Pages:   E5859
DOI:   10.1073/pnas.1805358115
Publication date:   26-Jun-2018
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