Spatial and topological control of receptor signaling using DNA nanotechnology

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The Chou group's research program explores design principles of self-assembling nanoscale devices. We currently focus on developing DNA as a medium for 3D nanofabrication, and on functionalizing engineered DNA nanostructures with lipids, polymers, proteins to interface them with biological systems. These DNA-scaffolded nanostructures are unique among synthetic nanomaterials in that their properties are sequence-programmable, which enables exquisite control over their structure and dynamics. Our group is using these capabilities to construct nanodevices that interface with cell membrane receptors for manipulating cell signaling pathways. Of particular interest to us are signaling pathways triggered through large-scale contacts, such as cell-cell and cell-pathogen interactions. These interactions induce cell activation states distinct from those induced using soluble ligands, but are especially difficult to recapitulate synthetically because they involve hetero-multivalent receptor-ligand interactions as well as their drastic spatial re-organization on the plasma membrane. Leveraging the programmability of DNA nanotechnology, this NSERC proposal aims to build an artificial cell membrane capable of spatial control over such multivalent receptor-ligand interactions. The specific aims are to: (1) establish the methodology of manufacturing an artificial cell membrane by combining DNA nanostructures with lipids, polymers, proteins, and microspheres; (2) understand how biological fluids, such as serum, influence features of the artificial cell membrane; (3) assess ability of the artificial cell membrane to toggle cell signaling as a function of its design features; (4) demonstrate ability to potentiate cell signaling via display of hetero-multivalent ligand arrays on the artificial cell membrane. The outcome will advance knowledge of cell signaling biology, generate a programmable cell-interfacing material for use by the biophysics, synthetic biology, and biomedical engineering community, and lead to next-generation technologies for cell manufacturing and for directing cell fate ex vivo and in vivo.