Journal
NANO LETTERS
Volume 20, Issue 3, Pages 1578-1589Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.9b04246
Keywords
Lipid nanoparticles; mRNA delivery; CAR T; T cell engineering
Categories
Funding
- Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Institutes of Health (NIH) Director's New Innovator Award [DP2 TR002776]
- National Institutes of Health [NCI R01 CA241661, NCI R37 CA244911]
- American Cancer Society [129784-IRG-16-188-38-IRG]
- Abramson Cancer Center (ACC)-School of Engineering and Applied Sciences (SEAS) Discovery Grant [P30 CA016520]
- 2018 AACR-Bayer Innovation and Discovery Grant [18-80-44-MITC]
- Tau Beta Pi Graduate Research Fellowship
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Chimeric antigen receptor (CAR) T cell therapy relies on the ex vivo manipulation of patient T cells to create potent, cancer-targeting therapies, shown to be capable of inducing remission in patients with acute lymphoblastic leukemia and large B cell lymphoma. However, current CAR T cell engineering methods use viral delivery vectors, which induce permanent CAR expression and could lead to severe adverse effects. Messenger RNA (mRNA) has been explored as a promising strategy for inducing transient CAR expression in T cells to mitigate the adverse effects associated with viral vectors, but it most commonly requires electroporation for T cell mRNA delivery, which can be cytotoxic. Here, ionizable lipid nanoparticles (LNPs) were designed for ex vivo mRNA delivery to human T cells. A library of 24 ionizable lipids was synthesized, formulated into LNPs, and screened for luciferase mRNA delivery to Jurkat cells, revealing seven formulations capable of enhanced mRNA delivery over lipofectamine. The top-performing LNP formulation, C14-4, was selected for CAR mRNA delivery to primary human T cells. This platform induced CAR expression at levels equivalent to electroporation, with substantially reduced cytotoxicity. CAR T cells engineered via C14-4 LNP treatment were then compared to electroporated CAR T cells in a coculture assay with Nalm-6 acute lymphoblastic leukemia cells, and both CAR T cell engineering methods elicited potent cancer-killing activity. These results demonstrate the ability of LNPs to deliver mRNA to primary human T cells to induce functional protein expression, and indicate the potential of LNPs to enhance mRNA-based CAR T cell engineering methods.
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