Multifunctional Polyphenol-Polymer Nanocomposite Hydrogel Targeting Inflammation, Oxidative Stress, and Infection in Diabetic Wounds.

Chronic diabetic wounds are characterized by prolonged inflammation, elevated reactive oxygen species (ROS), impaired angiogenesis, and delayed healing, often leading to tissue necrosis and amputation. Conventional wound dressings rarely address oxidative stress, dysregulated inflammation, bacterial infection, and local hyperglycemia simultaneously. Here, we developed a multifunctional nanoplatform consisting of tannic acid (TA)-complexed chitosan-polyethylenimine-phenylboronic acid (CPB-TA) nanoparticles embedded within a thermoresponsive poly(N-isopropylacrylamide-co-acrylic acid) [P(NIPAm-co-AAc)] hydrogel. CPB-TA nanoparticles exhibit dual cfDNA-scavenging and antioxidant activity, sequestering cfDNA through combined cationic binding and polyphenol interactions, and reducing ROS via complementary antioxidant mechanisms, thereby dampening inflammatory signaling and protecting reparative cells. The phenylboronic acid groups reversibly capture glucose through dynamic boronate ester bonds, helping to alleviate local hyperglycemia. The hydrogel matrix is designed to be responsive to body temperature, promoting localized delivery of CPB-TA at the wound site. In vitro, CPB-TA nanoparticles promoted macrophage polarization from M1 to M2, protected endothelial cells from oxidative damage, and exhibited antibacterial activity against Escherichia coli and Staphylococcus aureus. In vivo, topical application of CPB-TA@hydrogel accelerated wound closure, enhanced re-epithelialization, and increased collagen deposition in non-infected and S. aureus-infected diabetic mouse models. This multifunctional, mechanism-targeted strategy provides a rational, disease-relevant approach for treating chronic diabetic wounds.