Controlling Assembly of Hybrid DNA Nanostructures into Higher‐Order Structures via Hydrophobicity

Hydrophobic interactions are one of the fundamental driving forces of self-assembly in living systems. It remains challenging to harness hydrophobicity to have a controllable and programmable assembly of DNA nanostructures. On the other hand, there is also a need to explore orthogonal hierarchical assembly strategies to be used as an additional toolset along with the traditional Watson-Crick base pairing to achieve complex superstructures. In this work, we rationally design and synthesize a series of low molecular weight hydrophobic molecules that are conjugated to single-stranded DNA strands. By incorporating these modified DNA strands into the precisely defined locations of DNA tiles and origami nanostructures, we achieve controlled hierarchical assembly driven by hydrophobic interaction. We demonstrate a versatile hydrophobicity-guided higher-order assembly strategy by employing strategically engineered DNA nanostructures of increasing complexity, ranging from simple DNA tiles to complex origami structures, functionalized with these small hydrophobic molecules as programmable building blocks.