Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering
- 1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- 2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected]
Abstract
Targeted lipid nanoparticles (tLNPs) enable efficient mRNA delivery to T cells, allowing for in situ generation of chimeric antigen receptor (CAR) T cells without ex vivo manipulation. This strategy has shown promising therapeutical efficacy in preclinical studies of cardiac fibrosis, cancer, and autoimmune diseases. While multiple T-cell surface receptors have been targeted across studies for tLNP-mediated in vivo CAR T-cell generation and exhibit diverse efficiencies, their comparative performance and the mechanisms underlying these differences remain unclear. Here, we systematically compared tLNPs with antibody-based moieties targeting T-cell receptors including CD2, CD4, CD5, CD7, CD8, or a CD4/8 dual-targeting combination under identical conditions, assessing their mRNA delivery efficiency in human T cells and PBMCs in vitro , and subsequently validating the best performer in vivo in humanized mice. Among all moieties tested, CD7-targeting tLNPs achieved the highest mRNA delivery to T cells and efficiently generated functional CAR T cells in vivo . Mechanistic analysis revealed that receptor internalization, rather than the receptor abundance, is the primary determinant of delivery efficiency, a property intrinsic to each receptor and largely independent of antibody clone. These findings provide a rational framework for selecting optimal targeting moiety to enable highly efficient in vivo CAR T-cell engineering. Highlights Targeting CD7 outperforms other receptors for tLNP-mRNA delivery to T cells Receptor abundance does not predict tLNP-mRNA delivery efficiency Receptor internalization kinetics governs tLNP-mRNA delivery efficiency CD7-targeting LNP-mRNA enables efficient in vivo CAR T-cell engineering Graphical Abstract
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BibTeX
@article{zeng2026rapid,
title = {{Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering}},
author = {Jianhao Zeng and Tyler Ellis Papp and Awurama Akyianu and Alejandra Bahena and Lanfranco Leo and Faris Halilovic and Hamideh Parhiz},
journal = {Journal of Controlled Release},
year = {2026},
month = may,
doi = {10.1016/j.jconrel.2026.115043},
url = {https://doi.org/10.1016/j.jconrel.2026.115043},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering
AU - Jianhao Zeng
AU - Tyler Ellis Papp
AU - Awurama Akyianu
AU - Alejandra Bahena
AU - Lanfranco Leo
AU - Faris Halilovic
AU - Hamideh Parhiz
PY - 2026
DA - 2026/05/21
JO - Journal of Controlled Release
DO - 10.1016/j.jconrel.2026.115043
UR - https://doi.org/10.1016/j.jconrel.2026.115043
AB - Targeted lipid nanoparticles (tLNPs) enable efficient mRNA delivery to T cells, allowing for in situ generation of chimeric antigen receptor (CAR) T cells without ex vivo manipulation. This strategy has shown promising therapeutical efficacy in preclinical studies of cardiac fibrosis, cancer, and autoimmune diseases. While multiple T-cell surface receptors have been targeted across studies for tLNP-mediated in vivo CAR T-cell generation and exhibit diverse efficiencies, their comparative performance and the mechanisms underlying these differences remain unclear. Here, we systematically compared tLNPs with antibody-based moieties targeting T-cell receptors including CD2, CD4, CD5, CD7, CD8, or a CD4/8 dual-targeting combination under identical conditions, assessing their mRNA delivery efficiency in human T cells and PBMCs in vitro , and subsequently validating the best performer in vivo in humanized mice. Among all moieties tested, CD7-targeting tLNPs achieved the highest mRNA delivery to T cells and efficiently generated functional CAR T cells in vivo . Mechanistic analysis revealed that receptor internalization, rather than the receptor abundance, is the primary determinant of delivery efficiency, a property intrinsic to each receptor and largely independent of antibody clone. These findings provide a rational framework for selecting optimal targeting moiety to enable highly efficient in vivo CAR T-cell engineering. Highlights Targeting CD7 outperforms other receptors for tLNP-mRNA delivery to T cells Receptor abundance does not predict tLNP-mRNA delivery efficiency Receptor internalization kinetics governs tLNP-mRNA delivery efficiency CD7-targeting LNP-mRNA enables efficient in vivo CAR T-cell engineering Graphical Abstract
SN - 0168-3659
SN - 1873-4995
ER -