Enzyme-manipulated hydrogelation of small molecules for biomedical applications

Enzyme-manipulated hydrogelation based on self-assembly of small molecules is an attractive methodology for development of functional biomaterials. Upon the catalysis of enzymes, small-molecular precursors are converted into assemblable building blocks, which arrange into high-ordered nanofibers via non-covalent interactions at the molecular level, and further trap water to form hydrogels at the macroscopic level. Such approach has numerous advantages of region- and enantioselectivity, and mild reaction conditions for encapsulation of biomedications or cells that are fragile to environmental change. In addition to the common applications as drug reservoirs or cell scaffolds, the utilization of endogenous enzymes as stimuli to initiate self-assembly in the living cells and tissue is considered as an intelligent spatiotemporally controllable hydrogelation strategy for biomedical applications. The enzyme-instructed in situ self-assembly and hydrogelation can modulate the cell behavior, and even present therapeutic bioactivities, which provides a new perspective in the field of disease treatment. In this review, we categorize distinct enzymatic stimuli and elaborate substrate design, catalytic characteristics, and mechanisms of self-assembly and hydrogelation. The biomedical applications in drug delivery, tissue engineering, bioimaging, and in situ gelation-produced bioactivity are outlined. Advantages and limitations regarding the state-of-the-art enzyme-driven hydrogelation technologies and future perspectives are also discussed. Hydrogel is a semi-solid soft material containing a large amount of water. Due to the features of adjustable flexibility, extremely porous architecture, and the high similarity of structure to natural extracellular matrices, the hydrogel has broad application prospects in biomedicine. In recent 20 years, enzyme-manipulated hydrogelation based on self-assembly of small molecules has developed rapidly as an attractive methodology for the construction of functional biomaterials. Upon the catalysis of enzymes, small-molecular precursors are converted into assemblable building blocks, which arrange into high-ordered nanofibers via non-covalent interactions at the molecular level, and further trap water to form hydrogels at the macroscopic level. This review summarized the characteristics of enzymatic hydrogel, as well as the traditional application and emerging prospect of enzyme-instructed self-assembly and hydrogelation.