Leveraging Protein–Ligand and DNA Interactions to Control Hydrogel Mechanics

Biomacromolecules can serve as molecularly precise building blocks for hydrogel materials, dictating material properties that depend on the chemical identity and interactions of the individual components. Herein, we introduce biomolecular hydrogels where ligand-functionalized DNA sequences form the hydrogel backbone and multivalent protein–ligand interactions form supramolecular cross-links. In these hydrogels, we can independently leverage the programmable rigidity of DNA (i.e., single-stranded vs double-stranded DNA) and defined protein–ligand binding affinities spanning >10 orders of magnitude to modulate the gel stiffness, stress relaxation, and shear thinning. We learn that (1) double-stranded networks have stiffness values up to 3 orders of magnitude greater than single-stranded networks and exhibit thermoresponsiveness and (2) the protein–ligand binding affinities and dissociation rate constants determine the network topologies and stress relaxation rates of the hydrogels. Finally, the hydrogels exhibit cytocompatibility and cell-type-specific degradation, where cells can migrate through the gels via interactions between the gels and their ligand-binding receptors. Together, this work demonstrates that varying the local chemical interactions of the hydrogel backbone and the supramolecular binding affinity of dynamic cross-links leads to cytocompatible hydrogels with tunable viscoelastic properties for applications in drug delivery and tissue engineering.