Recent advances in fabrication strategies, functional modulation and healthcare applications of native protein-based hydrogels

Abstract

Native protein-based hydrogels not only possess all advantages of their denatured analogues such as exceptional biocompatibility and low toxicity, but also retain the intrinsic function of the protein building block. Therefore, they exhibit novel favorable properties including inherent bioactivity and reversible sol–gel transformation behavior. As such, they have emerged as versatile biomaterials widely used in the biomedical field. This review provides a comprehensive and up-to date overview of design strategies, formation mechanisms, and healthcare applications of native protein-based hydrogels. We systematically summarize the key cross-linking strategies for fabricating reversible native protein-based hydrogels, with particular emphasis on how these interactions govern hydrogel formation and their functionality. We highlight recent advances in fabricating these hydrogels through chemical cross-linking, physical cross-linking, metal coordination, fusion protein design, key interface redesign, de novo design, and modular design strategies, which enable precise control over hierarchical architecture, stimuli-responsiveness, and biomechanical properties. Furthermore, we explore the diverse healthcare applications of these hydrogels, with emphasis on drug delivery, wound healing, and tissue engineering. Finally, we discuss perspectives on future directions, including the integration of computational modeling, machine learning, and high-throughput experimentation to enable rational design of smart, multifunctional native protein-based hydrogels with tailored performances for next-generation biomedical applications. Design strategies and healthcare applications of native protein-based hydrogels