Using mRNA-LNP technology to manipulate conventional dendritic cell biology — ASN Events
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  2. Parallel Symposium A: DC Biology, Technologies and Therapeutic Opportunities
  3. Using mRNA-LNP technology to manipulate conventional dendritic cell biology

Using mRNA-LNP technology to manipulate conventional dendritic cell biology (141638)

Justine Mintern 1 , Christophe Macri 1 , Cassandra Ouslinis 2 , Yiqui Yang 2 , Kenny Chin 2 , India-Sophia Line 2 , Manjit Singh 3 , Angus Johnston 3
  1. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
  2. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
  3. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

First-generation messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have demonstrated clinical efficacy; however, the magnitude and durability of the immune responses they elicit remain suboptimal. Here, we have employed innovative strategies to engineer mRNA-LNP vaccines that specifically exploit the biology of conventional type 1 dendritic cells (cDC1s). First, we developed mRNA-LNPs encoding immune-modulatory molecules and identified transcription factor-encoding mRNA-LNPs (mRNA-LNP-TFs) capable of reprogramming cDC1-like cells in vivo. Coadministration of mRNA-LNP-TFs with low doses of antigen markedly enhanced CD8+ T cell immunity, resulting in improved vaccination outcomes in models of bacterial infection and tumour clearance. Second, we directly targeted mRNA-LNPs to cDC1s or to both cDC1s and cDC2s. To achieve this, we generated antibody-conjugated mRNA-LNPs directed against receptors highly expressed on these dendritic cell subsets. Targeted delivery significantly increased mRNA-LNP uptake and mRNA expression in cDC1s and cDC2s following both intramuscular and intravenous administration. These DC-targeted mRNA-LNPs were engineered either to enhance DC immunogenicity or, alternatively, to induce DC killing and depletion. In summary, mRNA-LNPs provide a versatile platform for manipulation of DC biology, enabling more sophisticated and effective immunotherapeutic vaccination strategies.