pH and glucose dual-responsive hydrogels for IL-4 and salvianolic acid A delivery to enhance diabetic wound healing

Chronic diabetic wounds exhibit impaired healing due to a complex interplay of pathological mechanisms, including persistent hyperglycemia, excessive matrix metalloproteinase-9 (MMP9) activity, and chronic inflammation, which disrupt tissue repair and regeneration. A central driver of this dysregulated healing is macrophage polarization imbalance, with excessive pro-inflammatory M1 and insufficient reparative M2 macrophages, prolonging inflammation and delaying tissue remodeling. To address these challenges, we developed a dual-responsive hydrogel composed of phenylboronic acid-functionalized polyethyleneimine (PEI-PBA), polyvinyl alcohol (PVA), and Benzaldehyde-PEG-Benzaldehyde (DF-PEG-DF) for controlled co-delivery of interleukin-4 (IL-4) and salvianolic acid A (SalA). This dynamically crosslinked hydrogel responds to the diabetic wound microenvironment, enabling pH- and glucose-triggered release. IL-4 promotes M2 macrophage repolarization, resolving inflammation and enhancing tissue repair, while SalA scavenges reactive oxygen species (ROS) and inhibits MMP9 activity, preserving extracellular matrix (ECM) integrity and supporting regeneration. In vivo, the hydrogel significantly accelerated wound closure in diabetic mice by promoting M2 polarization and reducing MMP9-mediated matrix degradation. This coordinated modulation of the inflammatory and proteolytic microenvironment attenuated inflammation, enhanced angiogenesis, and increased collagen deposition, collectively facilitating tissue regeneration. These findings suggest this intelligent hydrogel is a promising therapeutic strategy for chronic diabetic wound healing with translational potential.