Selection of DNA nanostructures for multivalent binding and drug delivery

forthcoming

In nanomedicine, patterns, shapes and mechanics are tuned to improve performance in applications such as drug delivery and pattern matching binders. A fundamental bottleneck is that structures need to be individually assembled and tested limiting the number that can be screened and likely missing structures with optimal performance. In this proposal we describe a new class of DNA nanostructures, assembled as diverse libraries of branched DNA wireframes with complex 3D shapes that fold from single stranded genomes. The structure genomes can be amplified and sequenced allowing us to test vast pools of structures in a single pot and amplify those with the best performance transforming nanomedicine from a design to a selection problem. This proposal has three objectives: First, we will refine the tools to assemble DNA structure libraries, perform selection and analyse the sequencing data to identify structures with optimal performance. Secondly, we aim to develop DNA based multivalent antibody alternatives by selecting DNA structures that can pattern multiple aptamers with respect to the epitope distribution on targets. We will target pathogenic proteins of both bacterial and viral origin to create a new route to rapid to develop / deploy binders for diagnostics. We also aim to construct multivalent binders that are specific for nucleosomes with multiple histone modifications. The interaction between DNA nanostructures and cells are controlled by geometry, mechanics and patterns of moieties. In our third objective we will use cell-type specific uptake a selection pressure to produce patterned DNA nanostructures that can deliver gene silencing RNA with specificity to diverse cell types, including cancer cells. By moving nanomedicine from single-pot rational design to an evolutionary approach inspired by how nature produces protein and RNA structures we hope to improve current applications and unlock new applications that can’t be approached with current methods.