Folding Double‐Stranded DNA into Designed Shapes with Triplex‐Forming Oligonucleotides

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Abstract
The compaction and organization of genomic DNA is a central mechanism in eukaryotic cells, but engineered architectural control over double‐stranded DNA (dsDNA) is notably challenging. Here, long dsDNA templates are folded into designed shapes via triplex‐mediated self‐assembly. Triplex‐forming oligonucleotides (TFOs) bind purines in dsDNA via normal or reverse Hoogsteen interactions. In the triplex origami methodology, these non‐canonical interactions are programmed to compact dsDNA (linear or plasmid) into well‐defined objects, which demonstrate a variety of structural features: hollow and raster‐filled, single‐ and multi‐layered, with custom curvatures and geometries, and featuring lattice‐free, square‐, or honeycomb‐pleated internal arrangements. Surprisingly, the length of integrated and free‐standing dsDNA loops can be modulated with near‐perfect efficiency; from hundreds down to only six bp (2 nm). The inherent rigidity of dsDNA promotes structural robustness and non‐periodic structures of almost 25.000 nt are therefore formed with fewer unique starting materials, compared to other DNA‐based self‐assembly methods. Densely triplexed structures also resist degradation by DNase I. Triplex‐mediated dsDNA folding is methodologically straightforward and orthogonal to Watson‐Crick‐based methods. Moreover, it enables unprecedented spatial control over dsDNA templates.

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