Enzyme-regulated biomineralization: Biological functions and advanced biomaterials for tissue regeneration

Enzyme-regulated biomineralization offers precise spatiotemporal control over tissue mineralization, overcoming key limitations of conventional regenerative therapies. This review systematically examines the underlying biological mechanisms, focusing on enzymatic regulation of phosphate metabolism, mineralization regulators, and matrix stabilization that orchestrate hierarchical mineral deposition. Organic matrices facilitate nanoconfinement-driven nucleation and spatially controlled mineralization through biochemical functionalization. These fundamental mechanisms have inspired the development of advanced enzyme-functionalized biomaterials, such as covalently immobilized hydrogels, physically entrapped nanocomposites, bioaffinity scaffolds, and stimuli-responsive 3D-printed constructs, which enable precisely tunable in situ mineralization. In clinical applications, such biomaterial systems demonstrate significant therapeutic potential, with critical-sized bone defects showing accelerated healing through biomimetic mineral-collagen alignment and enzyme-mediated enamel restoration achieving both hardness recovery and reduced secondary caries incidence. Current limitations primarily involve enzymatic stability, immunogenicity, and manufacturing scalability. Emerging solutions focus on gene-enzyme hybrid platforms and intelligent responsive systems for personalized regenerative approaches. The synergistic integration of biological principles with materials science provides a transformative foundation for developing next-generation therapeutic strategies.