Engineered T cells expressing chimeric antigen receptors (CARs) have been proven as efficacious therapies against selected hematological malignancies. However, the approved CAR T cell therapeutics strictly rely on viral transduction, a time- and cost-intensive procedure with possible safety issues. Therefore, the direct transfer of transcribed CAR-mRNA into T cells is pursued as a promising strategy for CAR T cell engineering. Electroporation (EP) is currently used as mRNA delivery method for the generation of CAR T cells in clinical trials but achieving only poor anti-tumor responses. Here, lipid nanoparticles (LNPs) were examined for CAR-mRNA delivery and compared with EP. LNP-CAR T cells showed a significantly prolonged efficacy in comparison with EP-CAR T cells as a result of extended CAR-mRNA persistence and CAR expression, attributed to a different delivery mechanism with less cytotoxicity and slower CAR T cell proliferation. Moreover, CAR expression and functionality of mRNA-LNP-derived CAR T cells were comparable to stably transduced CAR T cells but were less exhausted. These results show that LNPs outperform EP and underline the great potential of mRNA-LNP delivery for CAR T cell modification as next-generation transient approach for clinical studies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663670 | PMC |
| http://dx.doi.org/10.1016/j.omtm.2023.101139 | DOI Listing |
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