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Protein self-assembly plays a vital role in a myriad of biological functions and in the construction of biomaterials. Although the physical association underlying these assemblies offers high specificity, the advantage often compromises the overall durability of protein complexes. To address this challenge, we propose a novel strategy that reinforces the molecular self-assembly of protein complexes mediated by their ligand. Known for their robust noncovalent interactions with biotin, streptavidin (SAv) tetramers are examined to understand how the ligand influences the mechanical strength of protein complexes at the nanoscale and macroscale, employing atomic force microscopy-based single-molecule force spectroscopy, rheology, and bioerosion analysis. Our study reveals that biotin binding enhances the mechanical strength of individual SAv tetramers at the nanoscale. This enhancement translates into improved shear elasticity and reduced bioerosion rates when SAv tetramers are utilized as cross-linking junctions within hydrogel. This approach, which enhances the mechanical strength of protein-based materials without compromising specificity, is expected to open new avenues for advanced biotechnological applications, including self-assembled, robust biomimetic scaffolds and soft robotics. 

Intrinsically disordered proteins (IDPs) are a class of proteins that lack stable three-dimensional structures. Despite their natural tendency to be disordered, precise modulations of molecular parameters (e.g., sequence, length) through biomolecular engineering tools and control of environmental conditions tailor the formation of dynamic self-assembled structures. In addition to designing structures that respond to external stimuli for specific biotechnological applications (e.g., biosensors), other applications require stable structures (e.g., engineered tissues, drug delivery vehicles) that resist unintended changes and disassembly across various environmental conditions, such as different concentrations and temperatures. This review provides a comprehensive understanding of the design and engineering principles that govern the self-assembly of biosynthetic IDPs and their stability. Specifically, elastin-like polypeptides (ELPs) are highlighted as a prominent example of biosynthetically designed, thermoresponsive IDPs. Examples include ELPs that form various self-assembled structures by themselves as ELP homopolymers or diblock copolymers, ELPs combined with other IDPs in diblock copolymers, and ELP-based polymer hybrids containing functional (bio)molecules. It is anticipated that the efforts to enhance the stability of self-assembled structures through the precise engineering of IDP-based polymers have expanded the potential for diverse biotechnological applications in tissue engineering, drug delivery, diagnostic assays, and biomedicine.