A bioinspired enzyme-responsive hydrogel for spatiotemporal control of macrophage reprogramming in chronic wounds

Background Chronic wounds remain a significant challenge in healthcare due to persistent inflammation and disrupted macrophage polarization. Objective In this study, we conducted a quantitative comparative analysis to assess how enzyme-responsive hydrogels influence macrophage behaviour and promote wound healing. Methods A structured comparative dataset was constructed from 182 screened studies, with eight preclinical investigations included for quantitative analysis, focusing on hydrogels responsive to matrix metalloproteinases (MMP), reactive oxygen species (ROS), and cathepsins. Results Wound closure rates ranged from 60% to 90% by day 14. ROS-responsive hydrogels accelerated early-stage healing, while MMP-responsive hydrogels provided more sustained effects. Hydrogels containing exosomes produced the best healing outcomes, while those containing nanozymes provided prolonged anti-inflammatory benefits. All hydrogel systems increased M2 macrophage marker expression and reduced pro-inflammatory cytokine levels. We identified key pathways, including redox regulation, extracellular matrix remodelling, and epigenetic mechanisms, that affect macrophage polarization. Conclusion Preclinical results are promising, challenges such as the lack of standardized measurement protocols and limited clinical studies remain. This study offers a data-driven framework for understanding enzyme-responsive hydrogels and identifies priorities for future research.