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bioRxiv · 10.1101/2025.06.25.661517

Langerhans Cell-targeted mRNA Delivery: A Strategy for Dose-Sparing and Enhanced Anti-Tumor Immunity

Klein, K.·Johnson, L.·Rica, R.·Sarcevic, M.·Carta, G.·Seiser, S.·Elbe-Buerger, A.·Langer, L.·Rahhal, N.·Rademacher, C.·Wawrzinek, R.·Quattrone, F.·Sparber, F.
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Abstract

Despite the success of mRNA therapeutics, challenges remain in optimizing immune responses and minimizing side effects. Cell-specific antigen delivery may help reduce required doses and improve vaccine efficacy. In this study, we report on the first targeted delivery system for mRNA to a specific subset of skin-resident antigen-presenting cells - Langerhans cells. By functionalizing lipid nanoparticles (LNPs) with a langerin-specific glycomimetic ligand, we achieve selective mRNA delivery to both murine and human primary Langerhans cells with minimal off-target uptake, at the same time resulting in significantly increased mRNA translation. This targeted mRNA delivery not only enhances antigen presentation and T cell responses but also enables dose-sparing and superior anti-tumor immunity compared to conventional immunization in a B16-OVA tumor model. Importantly, our platforms high compatibility with various lipid nanoparticle formulations offers a flexible and precise tool for skin-directed mRNA delivery.

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Klein, K., Johnson, L., Rica, R., Sarcevic, M., Carta, G., Seiser, S., Elbe-Buerger, A., Langer, L., Rahhal, N., Rademacher, C., Wawrzinek, R., Quattrone, F., Sparber, F.. 2025-06-27. Langerhans Cell-targeted mRNA Delivery: A Strategy for Dose-Sparing and Enhanced Anti-Tumor Immunity. https://doi.org/10.1101/2025.06.25.661517

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