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We develop an enzymatic mineralization system (EMS) that achieves enamel regeneration by directing the hierarchical assembly of hydroxyapatite (HAP). Within the EMS, the alkaline phosphatase hydrolyzes \u03b2\u2010glycerophosphate (\u03b2\u2010GP), triggering the mineralization reaction of calcium phosphate (CaP) and controlling its structural evolution. The mineralization process is characterized by a series of spatiotemporal events, in which CaP prenucleation clusters initially form and transform into HAP nanorod building blocks; these units then hierarchically self\u2010assemble into microscale crystalline bundles that resemble native enamel rods. Mechanistically, differential adsorption of \u03b2\u2010GP on the (100) and (002) facets of HAP, together with facet\u2010dependent enzymatic cleavage of surface\u2010bound \u03b2\u2010GP, generates high\u2010energy facets and interfacial energy differences that drive the hierarchical assembly, beginning with\n                    <jats:italic>c<\/jats:italic>\n                    \u2010axis\u2013oriented attachment followed by lateral aggregation. Extending this new strategy to enamel remineralization, the EMS restores the native microstructure and essential mechanical properties. Moreover, a hydrogel\u2010based EMS demonstrates clinical translatability through effective in vivo repair. This paradigm of interfacial energy\u2013modulated assembly provides a robust blueprint for the bottom\u2010up construction of complex, high\u2010performance biomimetic materials.\n                  <\/jats:p>","DOI":"10.1002\/advs.78180","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:43:13Z","timestamp":1791517393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatiotemporal Regulation of Hierarchical Assembly of Hydroxyapatite for Enamel Remineralization"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-4296","authenticated-orcid":false,"given":"Zhenhang","family":"Tang","sequence":"first","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases Zhejiang Key Laboratory of Oral Biomedical, Zhejiang\u2010Singapore International 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Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases Zhejiang Key Laboratory of Oral Biomedical, Zhejiang\u2010Singapore International Joint Laboratory of Oral Bioengineering, Zhejiang Clinovation Pride Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases Zhejiang Key Laboratory of Oral Biomedical, Zhejiang\u2010Singapore International Joint Laboratory of Oral Bioengineering, Zhejiang Clinovation Pride Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province  Hangzhou 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