Orthogonal Multiple Hydrogen Bonds of Nucleobases Enable Precise Tunability of DNA‐Polymer Nanostructures

Abstract DNA‐polymer nanostructures manifest enhanced stability and chemical diversity for various applications such as sensing, imaging, and immune modulation. However, the functionality of the hydrophobic polymer in the core is often disregarded, leading to limited property tunability of DNA‐polymer nanostructures. Herein, we have successfully fabricated tunable DNA‐polymer nanostructures by harnessing orthogonal multiple hydrogen bonds (MHBs) within both the core and shell domains. Distinct DNA‐polymer nanostructures, consisting of hydrophobic nucleobase‐containing polymers and hydrophilic DNAs, have been rationally designed and successfully constructed. The DNA‐polymer nanostructures undergo the controlled morphological transformation triggered by hydrophobic nucleobase‐containing polymers and surface functionalization by hydrophilic DNA chains. Owing to the heterogeneous backbone structures, distinct repeat unit spacing, and different hydrophilicity, the robust MHB interactions for complementary DNAs and nucleobase‐containing polymers are highly selective and orthogonal. Most significantly, the reported core‐driven morphological transformation and surface functionalization of the shell layer are general to expand the structural and properties tunability of DNA nanostructures with different DNA sequences. This work provides an efficient and novel route to precisely modulating DNA‐polymer core‐shell nanostructures by exploiting the underexplored hydrophobic core through orthogonal MHBs.