Designing synthetic protein hydrogels with tailored mechanical properties similar to naturally occurring tissues is an eternal pursuit in tissue engineering and stem cell and cancer research. However, it remains challenging to correlate the mechanical properties of protein hydrogels with the nanomechanics of individual building blocks. Here we use single-molecule force spectroscopy, protein engineering and theoretical modeling to prove that the mechanical properties of protein hydrogels are predictable based on the mechanical hierarchy of the cross-linkers and the load-bearing modules at the molecular level. These findings provide a framework for rationally designing protein hydrogels with independently tunable elasticity, extensibility, toughness and self-healing. Using this principle, we demonstrate the engineering of self-healable muscle-mimicking hydrogels that can significantly dissipate energy through protein unfolding. We expect that this principle can be generalized for the construction of protein hydrogels with customized mechanical properties for biomedical applications.

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Most natural biomolecules may exist in either of two enantiomeric forms. Although in nature, amino acid biopolymers are characterized by l-type homochirality, incorporation of d-amino acids in the design of self-assembling peptide motifs has been shown to significantly alter enzyme stability, conformation, self-assembly behavior, cytotoxicity, and even therapeutic activity. However, while functional metabolite assemblies are ubiquitous throughout nature and play numerous important roles including physiological, structural, or catalytic functions, the effect of chirality on the self-assembly nature and function of single amino acids is not yet explored. Herein, we investigated the self-assembly mechanism of amyloid-like structure formation by two aromatic amino acids, phenylalanine (Phe) and tryptophan (Trp), both previously found as extremely important for the nucleation and self-assembly of aggregation-prone peptide regions into functional structures. Employing d-enantiomers, we demonstrate the critical role that amino acid chirality plays in their self-assembly process. The kinetics and morphology of pure enantiomers is completely altered upon their coassembly, allowing to fabricate different nanostructures that are mechanically more robust. Using diverse experimental techniques, we reveal the different molecular arrangement and self-assembly mechanism of the dl-racemic mixtures that resulted in the formation of advanced supramolecular materials. This study provides a simple yet sophisticated engineering model for the fabrication of attractive materials with bionanotechnological applications.

Hydrogel-based devices are widely used as flexible electronics, biosensors, soft robots, and intelligent human-machine interfaces. In these applications, high stretchability, low hysteresis, and anti-fatigue fracture are essential but can be rarely met in the same hydrogels simultaneously. Here, we demonstrate a hydrogel design using tandem-repeat proteins as the cross-linkers and random coiled polymers as the percolating network. Such a design allows the polyprotein cross-linkers only to experience considerable forces at the fracture zone and unfold to prevent crack propagation. Thus, we are able to decouple the hysteresis-toughness correlation and create hydrogels of high stretchability (~1100%), low hysteresis (< 5%), and high fracture toughness (~900 J m −2). Moreover, the hydrogels show a high fatigue threshold of~126 J m −2 and can undergo 5000 load-unload cycles up to 500% strain without noticeable mechanical changes. Our study provides a general route to decouple network elasticity and local mechanical response in synthetic hydrogels.

The formation of ordered nanostructures by metabolites is gaining increased interest due to the simplicity of the building blocks and their natural occurrence. Specifically, aromatic amino acids possess the ability to form ordered supramolecular interactions due to their limited solubility in aqueous solution. Unexpectedly, L-tyrosine (L-Tyr) is almost 2 orders of magnitude less soluble in water compared to L-phenylalanine (L-Phe). However, the underlying mechanism is not fully understood as L-Tyr is more polar. Here, we explore the utilization of insoluble tyrosine assemblies for technological applications and their molecular basis by manipulating the basic building blocks of tightly packed dimers. We show that the addition of an amyloid inhibition agent increases L-Tyr solubility due to the disruption of the dimer formation. The molecular organization grants the L-Tyr crystal higher thermal stability and mechanical properties between three amino acids. Additionally, L-Tyr crystals are shown to generate high and stable piezoelectric power outputs under mechanical pressure in a sandwich device. By incorporating the rigid L-Tyr crystals into a soft polymer, a mechanoresponsive bending composite was fabricated. Furthermore, the L-Tyr crystalline needles exhibit an active photowaveguiding property, making them promising candidates for the generation of photonic biomaterial-based devices. The present work exemplifies a feasible strategy to explore physical properties of supramolecular self-assemblies comprises minimalistic naturally occurring building blocks and their applications in energy harvesting, photonic devices, stretchable electronics, and soft robotics.

Fast and strong bio-adhesives are in high demand for many biomedical applications, including closing wounds in surgeries, fixing implantable devices, and haemostasis. However, most strong bio-adhesives rely on the instant formation of irreversible covalent crosslinks to provide strong surface binding. Repositioning misplaced adhesives during surgical operations may cause severe secondary damage to tissues. Here, we report hydrogel tapes that can form strong physical interactions with tissues in seconds and gradually form covalent bonds in hours. This timescale-dependent adhesion mechanism allows instant and robust wet adhesion to be combined with fault-tolerant convenient surgical operations. Specifically, inspired by the catechol chemistry discovered in mussel foot proteins, we develop an electrical oxidation approach to controllably oxidize catechol to catecholquinone, which reacts slowly with amino groups on the tissue surface. We demonstrate that the tapes show fast and reversible adhesion at the initial stage and ultrastrong adhesion after the formation of covalent linkages over hours for various tissues and electronic devices. Given that the hydrogel tapes are biocompatible, easy to use, and robust for bio-adhesion, we anticipate that they may find broad biomedical and clinical applications.

Many load-bearing tissues, such as muscles and cartilages, show high elasticity, toughness, and fast recovery. However, combining these mechanical properties in the same synthetic biomaterials is fundamentally challenging. Here, we show that strong, tough, and fast-recovery hydrogels can be engineered using cross-linkers involving cooperative dynamic interactions. We designed a histidine-rich decapeptide containing two tandem zinc binding motifs. Because of allosteric structural change-induced cooperative binding, this decapeptide had a higher thermodynamic stability, stronger binding strength, and faster binding rate than single binding motifs or isolated ligands. The engineered hybrid network hydrogels containing the peptide-zinc complex exhibit a break stress of ~3.0 MPa, toughness of ~4.0 MJ m−3, and fast recovery in seconds. We expect that they can function effectively as scaffolds for load-bearing tissue engineering and as building blocks for soft robotics. Our results provide a general route to tune the mechanical and dynamic properties of hydrogels at the molecular level.

Peptide assemblies are ideal components for eco-friendly optoelectronic energy harvesting devices due to their intrinsic biocompatibility, ease of fabrication, and flexible functionalization. However, to date, their practical applications have been limited due to the difficulty in obtaining stable, high-performance devices. Here, it is shown that the tryptophan-based simplest peptide cycloglycine-tryptophan (cyclo-GW) forms mechanically robust (elastic modulus up to 24.0 GPa) and thermally stable up to 370 °C monoclinic crystals, due to a supramolecular packing combining dense parallel β-sheet hydrogen bonding and herringbone edge-to-face aromatic interactions. The directional and extensive driving forces further confer unique optical properties, including aggregation-induced blue emission and unusual stable photo-luminescence. Moreover, the crystals produce a high and sustained opencircuit voltage (1.2 V) due to a high piezoelectric coefficient of 14.1 pC N−1. These findings demonstrate the feasibility of utilizing self-assembling peptides for fabrication of biointegrated microdevices that combine high structural stability, tailored optoelectronics, and significant energy harvesting properties.