A spatiotemporally programmed, matrix metalloproteinase-9-responsive hyaluronic acid/polyglutamate hydrogel for...

In chronic diabetic wounds, immune microenvironmental dysregulation arises from hyperglycemia, accumulation of reactive oxygen species (ROS), and overexpression of matrix metalloproteinase-9 (MMP-9), leading to an imbalance in macrophage M1/M2 polarization and a dysregulated inflammatory response impeding wound healing. To address this challenge, we developed an MMP-9-activated, multimodal glycopeptide hydrogel (HPDM) that forms in situ via photocontrolled polymerization as a time-responsive drug-delivery system. Leveraging the elevated MMP-9 activity in the wound microenvironment, metformin-loaded gelatin microspheres (Met@GMs) are specifically released in response. Additionally, doxycycline (Dox) is incorporated into the hydrogel to establish a temporally programmed therapeutic regimen prioritizing antimicrobial and anti-inflammatory activity. The HPDM hydrogel achieves >90% bactericidal rates against both E. coli and S. aureus along with significant biofilm inhibition. The biomimetic glycopeptide architecture recapitulates the topology of the extracellular matrix (ECM) and helps restore its dynamic homeostasis. In a diabetic wound model, HPDM significantly accelerated wound healing compared to controls, reduced ROS levels to approximately 0.09-fold of the control, and enhanced anti-inflammatory IL-10 expression to about 240% of the control. It remodels the wound microenvironment and accelerates the transition from the inflammatory to the proliferative phase in diabetic wounds, offering an innovative therapeutic approach centered on spatiotemporal modulation immune microenvironment.