Seiser, S. | bioRxiv Science

bioRxiv2025

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

immunology↗

bioRxiv2024

Carbon Dioxide Controls Fungal Fitness and Skin Tropism of Candida auris

The pronounced skin tropism and pan-antifungal resistance traits of the fungal pathogen Candida auris stand out as a serious health threat. Here, we show that a carbonic sensing pathway (CSP) promotes development of resistance to amphotericin B through a reactive oxygen species (ROS) response, as well as ectopic cell wall and membrane lipid homeostasis. Mechanistically, the transcription factor Rca1 acts in cooperation with Efg1 to control the expression and activity of the carbonic anhydrase Nce103 as a key effector component. The conversion of carbon dioxide to bicarbonate provides a direct link to energy metabolism, facilitating colonization and growth on skin tissues. Native mouse and human skin models unequivocally show that the CSP is essential for maintaining skin tropism as well as fungal fitness. Curiously, upon ablation of Rca1 and Efg1, C. auris debilitates efficient growth on native skin. Collectively, our findings highlight critical roles of the CSP in C. auris skin tropism and antifungal drug resistance. The work suggests therapeutic options for disrupting skin colonization and thus preventing infections. Highlights{checkmark} Proteo-transcriptomics links a carbonic sensing pathway (CSP) to C. auris multidrug resistance {checkmark}The Nce103 carbonic anhydrase controls drug resistance as a key component of the CSP {checkmark}The transcription factors Rca1 and Efg1 control Nce103 and link CSP with C. auris skin tropism {checkmark}CSP acts through ectopic ROS response, cell wall architecture and membrane lipid function {checkmark}CSP is required for C. auris fitness and efficient growth and colonization of skin tissues Result contents{checkmark} Integrated omics reveals multidrug-resistant mechanisms in C. auris {checkmark}CO2-sensing controls amphotericin B resistance (AMBR) traits through Rca1 and Efg1 {checkmark}The carbonic anhydrase Nce103 governs susceptibility to amphotericin B {checkmark}The CSP influences AMBR by maintaining reactive oxygen species homeostasis {checkmark}The CSP controls AMBR via cell membrane and cell wall remodelling {checkmark}The CSP regulates fungal fitness through controlling energy metabolism {checkmark}C. auris requires the CSP for skin colonization

microbiology↗