Dressing up Nanoparticles: A Membrane Wrap to Induce Formation of the Virological Synapse

Next-generation nanoparticle-based drug delivery systems require the ability to target specific organelles or subcellular regions in selected target cells. Human immunodeficiency virus type I (HIV-1) particles are evolutionarily optimized nanocarriers that have evolved to avoid intracellular degradation and achieve enrichment at the synapse between mature dendritic cells (mDCs) and T cells by subverting cellular trafficking mechanisms. This study demonstrates that integration of the glycosphingolipid, GM3, in a membrane around a solid nanoparticle (NP) core is sufficient to recapitulate key aspects of the virus particle trafficking in mDCs. GM3-presenting artificial virus NPs (GM3-AVNs) accumulate in CD169+ and CD81+ nonlysosomal compartments in an actin-dependent process that mimics the sequestration of HIV-1. Live-cell optical tracking studies reveal a preferential recruitment and arrest of surface scanning CD4+ T cells in direct vicinity to the AVN-enriched compartments. The formed mDC–T cell conjugates exhibit strong morphological similarities between the GM3-AVN-containing mDC–T cell synapse and the HIV-1 virological synapse, indicating that GM3–CD169 interactions alone are sufficient for establishing the mDC–T cell virological synapse. These results emphasize the potential of the GM3-AVN approach for providing therapeutic access to a key step of the host immune responseformation of the synaptic junction between an antigen-presenting cell (mDC) and T cellsfor modulating and controlling immune responses.