A Pathology-Responsive Hydrogel with On-Demand Ion Release for Microenvironment Remodeling and Diabetic Wound Regeneration.

Abstract

The healing of diabetic wounds is often impeded by severe bacterial infections, persistent inflammation, excessive accumulation of reactive oxygen species (ROS), and abnormal matrix degradation. Although conventional free silver nanoparticles (AgNPs) possess broad-spectrum antimicrobial activity, their inherent tendency to aggregate and inactivate, as well as its high cytotoxicity limits their clinical application. Moreover, a single bactericidal strategy is insufficient to completely reverse the complex pathogenic microenvironment of the wound. To address these challenges, this study developed a dual-polyphenol biomimetic extracellular matrix (ECM) composite hydrogel with matrix metalloproteinase-9 (MMP-9) and pH-responsive properties, aimed at achieving spatiotemporal precision intervention and active microenvironment remodeling in diabetic wounds. This system employs caffeic acid-modified gelatin and dopamine-modified sodium alginate as a dynamically cross-linked scaffold, incorporated with AgNPs-anchored zinc-aluminum layered double hydroxide (ZnAl-LDH@Ag), that can precisely match the dynamic pathological evolution of the wound. The hydrogel exhibits pathology-adaptive behavior through two complementary mechanisms: gradual MMP-9-mediated remodeling of the gelatin network and infection-associated pH-responsive ion release. MMP-9-mediated degradation enables sustained exposure of ZnAl-LDH@Ag and prolonged matrix remodeling, whereas the acidic microenvironment promotes on-demand release of antibacterial Ag+ and regenerative Zn2+ ions. Additionally, polyphenol moieties provide antioxidant and anti-inflammatory regulation during wound healing. By integrating two-dimensional inorganic layered materials (ZnAl-LDH) with conventional metal nanocrystals (AgNPs), this strategy resolves the clinical paradox in silver-based therapies: the difficulty of balancing high bactericidal activity with low cytotoxicity. In summary, this pathology-driven therapeutic platform enables multimodal synergistic therapy for antioxidant protection, infection control, and tissue regeneration, providing a theoretical foundation and design perspectives for the development of advanced dressings for complex chronic wounds.