BiomaterialsJul 13, 2026

Adding signaling proteins to targeted lipid nanoparticles improves T cell engineering in living organisms

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 14, 2026

Abstract

IL-7 co-presentation on lipid nanoparticles significantly enhances uptake and transgene expression in primary human T cells.

Antibody-conjugated lipid nanoparticles (LNPs) have been developed to deliver signals necessary for T cell activation.
The introduction of interleukin-7 (IL-7) alongside anti-CD3 and anti-CD28 antibodies enables a tri-signal presentation at the T cell interface.
IL-7-conjugated LNPs lead to greater particle uptake and transgene expression compared to LNPs with antibodies alone or soluble IL-7.
In naive T cells, IL-7-conjugated LNPs promote both proliferation and transgene expression, increasing the proportion of transfected cells.
In vivo, these LNPs preferentially transfect splenic T cells while reducing transfection in hepatic T cells, with no change in overall biodistribution.
As a proof of concept, IL-7-conjugated LNPs successfully deliver CAR mRNA, resulting in functional CAR-expressing T cells capable of targeting specific antigens.

Simplified

T lymphocytes are attractive cellular targets for gene therapy and cell engineering, due to their critical role in adaptive immunity; however, efficient in vivo T cell transfection remains challenging. Antibody-conjugated lipid nanoparticles (LNPs) have emerged as a non-viral approach to engage T cells in vivo, but existing platforms primarily deliver activation signals 1 and 2 and lack cytokine-mediated signal 3 support. Here, we introduce a signal 3-augmented LNP design in which interleukin-7 (IL-7) is co-conjugated to the LNP surface with anti-CD3 and anti-CD28 antibodies, enabling localized tri-signal presentation at the T cell-nanoparticle interface. IL-7 co-presentation by these anti-CD3/anti-CD28/IL-7 LNPs significantly enhances particle uptake and transgene expression in primary human T cells compared to antibody-only LNPs or equivalent supplementation with soluble IL-7, demonstrating the importance of particle-bound signal 3 delivery. In naïve T cells, IL-7-conjugated LNPs promote coupled proliferation and transgene expression, increasing the fraction of transfected cells within both proliferating and non-proliferating populations. In vivo, IL-7-conjugated LNPs bias functional mRNA transfection toward splenic T cells while reducing hepatic T cell transfection, without altering overall organ-level biodistribution. As a proof of concept, IL-7-conjugated LNPs deliver chimeric antigen receptor (CAR) mRNA to generate functional CAR-expressing T cells in vivo, enabling antigen-specific target cell depletion. Together, these results establish cytokine signal 3 co-presentation as an effective design approach for T cell-targeted mRNA LNPs, resulting in enhanced engagement, uptake, and transfection in T cells in vivo.

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Funding

Competing interests

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hai-Quan Mao reports financial support was provided by National Institutes of Health National Cancer Institute. Hai-Quan Mao reports financial support was provided by National Institute of Biomedical Imaging and Bioengineering. Hai-Quan Mao reports financial support was provided by National Institutes of Health. Jamie Spangler reports financial support was provided by Bladder Cancer Action Network. Jamie Spangler reports financial support was provided by The Leona M and Harry B Helmsley Charitable Trust. Emily Ariail reports financial support was provided by Achievement Rewards for College Scientists Foundation Inc. Sydney Shannon reports financial support was provided by National Science Foundation. Sydney Shannon reports financial support was provided by National Institutes of Health. Daniel Antov reports financial support was provided by National Science Foundation. Benjamin Biggs reports financial support was provided by Quad Fellowship. Benjamin Biggs reports financial support was provided by American Australian Association Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

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Adding signaling proteins to targeted lipid nanoparticles improves T cell engineering in living organisms

Abstract

Full Text

Funding

Competing interests

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