Lipid nanoparticle mRNA delivery preserves CAR T cell cytotoxicity and limits exhaustion compared to electroporation

Picht S, Farrera-Sal M, Hiller AL, Brumhard S, Klaas AM, Schulenberg S, Friedrich R, Scholz C, Hemmerling L, Simon DN, Krönke G, Pichon C, Sander LE, Volk HD, Gossen M, Schmueck-Henneresse M, Drzeniek NM (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Molecular Therapy - Nucleic Acids Elsevier (Cell Press)

Book Volume: 37

Article Number: 102929

Journal Issue: 2

DOI: 10.1016/j.omtn.2026.102929

Abstract

Chimeric antigen receptor (CAR) T cells offer a promising strategy for the treatment of autoimmune diseases. However, clinical translation is limited by the high cost, complexity, and poor scalability of current manufacturing, restricting broad patient access and persisting safety concerns including insertional mutagenesis risk from integrating vectors and uncontrolled long-term CAR T cell persistence. In-vitro -transcribed (IVT) mRNA enables transient, non-integrating CAR expression with improved safety and scalability, making it particularly suited for non-malignant indications where prolonged persistence may not be required. Here, we systematically compare two IVT mRNA delivery platforms, electroporation and lipid nanoparticles (LNPs), for transient CAR T cell engineering in primary human T cells using single-cell transcriptomics and functional cell assays. We show that electroporation yields higher transfection efficiency and more sustained CAR surface expression, whereas LNP delivery reduces stress- and senescence-related transcriptional signatures as well as exhaustion marker expression, while enhancing antigen-driven activation, chemotactic responses, and cytotoxic function. Our comparative analysis highlights that the mode of mRNA delivery is associated with distinct transcriptional signatures and functional properties of CAR T cells, providing a framework to guide future development of mRNA-based approaches. These insights support LNP-mediated delivery as a functionally favorable strategy for transient CAR T cell engineering in autoimmune disease and beyond.

Involved external institutions

Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) University of Orléans / Université d'Orléans FR France (FR) Helmholtz-Zentrum Hereon DE Germany (DE)

How to cite

APA:

Picht, S., Farrera-Sal, M., Hiller, A.L., Brumhard, S., Klaas, A.M., Schulenberg, S.,... Drzeniek, N.M. (2026). Lipid nanoparticle mRNA delivery preserves CAR T cell cytotoxicity and limits exhaustion compared to electroporation. Molecular Therapy - Nucleic Acids, 37(2). https://doi.org/10.1016/j.omtn.2026.102929

MLA:

Picht, Samira, et al. "Lipid nanoparticle mRNA delivery preserves CAR T cell cytotoxicity and limits exhaustion compared to electroporation." Molecular Therapy - Nucleic Acids 37.2 (2026).

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