Enzyme-Programmable DNA-PEG Hydrogel Spatiotemporally Regulates Bone Regeneration Microenvironment
Conventional hydrogel drug delivery systems are limited in recapitulating the natural spatiotemporal progression of bone regeneration due to their passive release mechanisms. Here, an enzyme-responsive deoxyribonucleic acid (DNA)-polyethylene 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)-cleavable peptide-crosslinked PEG networks conjugated with actin-stabilized vascular endothelial growth factor (VEGF)-binding 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-stabilized 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-mediated 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-phase bone regeneration, offering new possibilities for complex tissue repair.
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