Tough natural materials such as nacre, bone, and silk exhibit multiscale hierarchical structures where distinct toughening mechanisms occur at each level of the hierarchy, ranging from molecular uncoiling to microscale fibrillar sliding to macroscale crack deflection. An open question is whether and how the multiscale design motifs of natural materials can be translated to the development of next-generation biomimetic hydrogels. To address this challenge, we fabricate strong and tough hydrogel with architected multiscale hierarchical structures using a freeze-casting–assisted solution substitution strategy. The underlying multiscale multimechanisms are attributed to the gel’s hierarchical structures, including microscale anisotropic honeycomb–structured fiber walls and matrix, with a modulus of 8.96 and 0.73 MPa, respectively; hydrogen bond–enhanced fibers with nanocrystalline domains; and cross-linked strong polyvinyl alcohol chains with chain-connecting ionic bonds. This study establishes a blueprint of structure-performance mechanisms in tough hierarchically structured hydrogels and can inspire advanced design strategies for other promising hierarchical materials.

Significance: There is a critical lack of therapeutic agents to treat infections caused by nongrowing persister forms of methicillin-resistant Staphylococcus aureus (MRSA). Although membrane-disrupting agents can kill persister cells, their therapeutic potential has been mostly overlooked because of low selectivity for bacterial versus mammalian membranes. We report that the clinically approved anthelmintic drug bithionol kills MRSA persisters by disrupting membrane lipid bilayers at concentrations that exhibit low levels of toxicity to mammalian cells. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Our results significantly enhance our understanding of bacterial membrane disruption and membrane selectivity.

Marine mussels achieve strong underwater adhesion by depositing mussel foot proteins (Mfps) that form coacervates during the protein secretion. However, the molecular mechanisms that govern the phase separation behaviors of the Mfps are still not fully understood. Here, we report that GK-16*, a peptide derived from the primary adhesive protein Mfp-5, forms coacervate in seawater conditions. Molecular dynamics simulations combined with point mutation experiments demonstrate that Dopa- and Gly- mediated hydrogen-bonding interactions are essential in the coacervation process. The properties of GK-16* coacervates could be controlled by tuning the strength of the electrostatic and Dopa-mediated hydrogen bond interactions via controlling the pH and salt concentration of the solution. The GK-16* coacervate undergoes a pH induced liquid-to-gel transition, which can be utilized for the underwater delivery and curing of the adhesives. Our study provides useful molecular design principles for the development of mussel-inspired peptidyl coacervate adhesives with tunable properties.