Enzymes, a class of highly efficient and specific catalysts in Nature, dictate a myriad of reactions that constitute various cascades in biological systems. There is growing evidence that many cellular reactions within metabolic pathways are catalyzed by matrix-associated multienzyme complexes, not via the free enzymes, verifying the vital effects of microenvironmental organization, which would reveal implications for the high efficiency, specificity, and regulation of metabolic pathways. The extracellular matrix (ECM), as the noncellular component, is composed of various proteins such as collagens, laminins, proteoglycans, and remodeling enzymes, playing the key role in tissue architecture and homeostasis. Hydrogels are defined as highly hydrated polymer materials and maintain structural integrity by physical and chemical force, which are thought of as the most suitable materials for matching the chemical, physical, and mechanical properties with natural ECM. As one specific type of soft and wet materials, hydrogels are suitable three-dimensional carriers to locally confine bioactive guests, such as enzymes, for molecular-level biological interactions. The efficient cascade catalysis can be realized by enzyme-laden hydrogels, which can potentially interact with cells and tissues by material-to-biology communication. In this Account, we present recent progress on the preparation of enzymatic bioactive hydrogels, including in situ coassembly, in situ cross-linking strategy, and in situ enzymatic radical polymerization technology, further promoting their applications on biomedical tissue engineering, biocatalytic health monitoring, and therapeutic research. First, we provide a brief introduction of the basic concept related to an enzymatic strategy in living systems and the importance of bioinspired enzyme-laden bioactive hydrogel systems. We discuss the difficulties of the fabrication of a bioactive hydrogel with a high catalytic efficiency, thereby providing the novel molecular design and regulation based on a noncovalent coassembly and in situ self-immobilization strategy to obtain the compartmentalized enzyme-laden structure. Then the applications of an enzyme-laden bioactive hydrogel for biocatalytic applications are discussed in detail. The enzyme-laden bioactive hydrogel can maintain the favorable perception and regulation behavior of enzymes with optimal enzymatic efficacy between this confined hydrogel network and a surrounding environment. A highlight to the advances in the responsively biocatalytic monitoring and regulation of bioactive hydrogel, including the enzymatic biomedical tissue engineering and health monitoring, enzymatic regulation of tumor reactive oxygen species and therapeutic research are given. Finally, the outlook of open challenges and future developments of this rapidly evolving field is provided. This Account with highlights of diverse enzyme-laden bioactive hydrogel systems not only provides interesting insights to understand the cascade enzymatic strategy of life but also inspires to broaden and enhance the molecular-level material design and bioapplications of existing enzymatic materials in chemistry, materials science, and biology.
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