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Here, an enzyme\u2010responsive deoxyribonucleic acid (DNA)\u2010polyethylene glycol (PEG) hydrogel is developed to actively coordinate the sequential processes of angiogenesis, osteogenesis, and mineralization through rational material design. The hydrogel integrates matrix metalloproteinase (MMP)\u2010cleavable peptide\u2010crosslinked PEG networks conjugated with actin\u2010stabilized vascular endothelial growth factor (VEGF)\u2010binding DNA strands, enabling spatiotemporally controlled therapeutic release. Upon implantation, MMPs trigger the hydrogel degradation, releasing VEGF to induce angiogenesis while simultaneously promoting osteogenic differentiation. The actin\u2010stabilized DNA framework maintains structural integrity during this stage, preventing premature phosphate release. Subsequent matrix remodeling liberates nuclease that catalyzes DNA to generate phosphate ions, which synergize with peptides in hydrogels and endogenous calcium to drive mineralization. Molecular dynamics simulations reveal the underlying mechanism of hydrogel\u2010mediated mineralization, demonstrating enhanced calcium phosphate formation. Such temporally controlled cascade significantly improves vascular density, osteogenic marker expression, and mineral deposition compared to controls. This work establishes a bioresponsive platform that dynamically interacts with the biological microenvironment to orchestrate multi\u2010phase bone regeneration, offering new possibilities for complex tissue repair.<\/jats:p>","DOI":"10.1002\/adma.202514461","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T06:49:27Z","timestamp":1762152567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Enzyme\u2010Programmable DNA\u2010PEG Hydrogel Spatiotemporally Regulates Bone Regeneration Microenvironment"],"prefix":"10.1002","volume":"38","author":[{"given":"Xiang","family":"Wu","sequence":"first","affiliation":[{"name":"Organoid Research Center Institute of Translational Medicine Shanghai University  Shanghai 200444 China"},{"name":"MedEng\u2010X Institutes National Center for Translational Medicine (Shanghai) SHU Branch Shanghai University  Shanghai 200444 China"},{"name":"School 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