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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