Langerhans cell-targeted mRNA delivery: A strategy for dose-sparing and enhanced antitumor immunity

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 a targeted delivery system for mRNA to a specific subset of skin-resident antigen-presenting cells: Langerhans cells. By functionalizing lipid nanoparticles 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 antitumor immunity compared with conventional immunization in a B16-OVA tumor model. Importantly, our platform's high compatibility with various lipid nanoparticle formulations offers a flexible and precise tool for skin-directed mRNA delivery.