Tuning endothelial cells into ‘professional’ antigen presenting endothelial cells by using lipid nanoparticles

Endothelial cells (ECs), lining the blood vessels, are active participants in various pathways, including angiogenesis, metabolism and immune cell infiltration, and are therefore interesting targets for anti-cancer therapies. Still, ECs remain understudied and undervalued mainly because of the lack of experimental tools for functional validation. Recently, a breakthrough in targeting ECs using lipid nanoparticles (LNPs) has made in vivo gene manipulation of ECs more feasible, opening new research opportunities. Here, we would like to manipulate ECs and tune them into ‘professional’ antigen presenting cells (APCs). For ECs to become professional APCs and capable of activating T cells, they need co-stimulators CD80 and CD86 to be expressed, which are often lacking. We will induce the expression of CD80/CD86 co-stimulators by transporting plasmid DNA (pDNA) to ECs using LNPs, however, this overexpression alone might not be enough to fully activate ECs in the context of the tumor microenvironment (TME). Tumor ECs (TECs) are part of the immunosuppressive TME, and have an immunosuppressive nature themselves. Silencing this immunosuppressive nature by short interference RNA (siRNA) could tune them more immunostimulatory. The combination strategy of overexpressing CD80/CD86 and silencing the immunosuppressive nature, would stimulate a stronger immune response towards the tumor and could improve traditional immunotherapy approaches.