Complex Donuts: Small Variations in DNA Sequence Dictate Pathway Complexity in DNA Nanotoroids

Abstract

Abstract The formation of higher‐order structures in natural biopolymers, such as polypeptides and nucleic acids, is governed by sequence specificity and monomer chemistry. Although nucleic acids can assemble into programmable nanostructures through base‐pairing interactions, their chemical diversity is limited to four nucleobases. DNA amphiphiles overcome this limitation by introducing orthogonal interactions through non‐nucleosidic modifications. These amphiphiles self‐assemble into diverse morphologies, such as spheres, fibers, or sheets, with closely packed, parallel DNA strands on their exterior. This unusual arrangement can give rise to emergent properties absent in simple DNA strands. Here, we show that the precise sequence of single‐stranded DNA, independent of double helix base‐pairing, can be used to program the self‐assembled morphology of DNA amphiphiles. Remarkably, small sequence variations can drive the formation of nonequilibrium DNA nanotoroids, rather than conventional morphologies. The DNA nanotoroids were formed as on‐pathway structures via a competitive mechanism, only when a toroid‐selective DNA sequence was used. They could be stabilized noncovalently by a small molecule cross‐linker or coassembly with a secondary DNA amphiphile. Molecular dynamics simulations demonstrated the dependence of toroid formation on the structure of the end π‐stacking unit. This work introduces a new class of DNA‐based nanotoroid materials with assembly properties controlled by unique sequences, akin to proteins, for applications in cell delivery, nanofiltration, nanoreactors, and materials templation.