A wound-reporting multiresponsive hydrogel with catalytic metal–polyphenol nanosheets and protease-responsive angiogenic depots for diabetic irradiated wound repair

Patients undergoing cancer treatment may have comorbidities such as diabetes, which compromise wound repair. Radiation-induced oxidative stress, inflammation, and microvascular dysfunction can aggravate hyperglycemia-associated oxidative injury, susceptibility to infection, and impaired angiogenesis, creating barriers to wound healing. However, biomaterial-based strategies addressing these multiple repair barriers remain limited. We developed a composite hydrogel based on phenylboronic-acid-grafted oxidized hyaluronic acid (OHA-PBA)/carboxymethyl chitosan (CMCS) and incorporating Cu–EGCG nanosheets, bromothymol blue (BTB), and deferoxamine-loaded gelatin microspheres (G@D). This system integrates semiquantitative visual pH indication with pH/ROS/MMP-9-responsive therapeutic release. Under combined stimulation with pH 5.0 and 5 mM H 2 O 2 , complete degradation occurred within 13.7 ± 1.90 h, while MMP-9-responsive deferoxamine (DFO) release reached 44.69 ± 1.38% at 120h in vitro . The optimized formulation containing 200 µg mL − 1 Cu–EGCG (HCC2B-G@D) reduced the proportion of DCFH-positive irradiated cells to 10.60 ± 1.15%, promoted an anti-inflammatory/M2-like macrophage phenotype, and decreased MRSA and E. coli counts by 4–5 log 10 units. Transcriptomic analysis indicated that its antibacterial activity involved cell-envelope disruption, oxidative damage, metabolic dysregulation, and virulence suppression. In vivo performance was evaluated in two complementary settings. In MRSA-infected wounds in Bama miniature pigs, HCC2B-G@D reduced the bacterial burden and promoted wound repair. In diabetic rats in which full-thickness wounds were created 2 days after local X-ray irradiation, HCC2B-G@D significantly accelerated wound closure and tissue regeneration under acute irradiation-impaired conditions. These effects were associated with reduced NF-κB-related inflammatory signaling, a molecular pattern consistent attenuated ferroptosis-associated changes and enhanced SLC7A11/GPX4-related antioxidant defense, and increased PI3K–AKT/HIF-1α/VEGF-related signaling. This study presents a multiresponsive smart-dressing strategy that integrates colorimetric pH monitoring, adaptive therapeutic delivery, and microenvironment regulation, with complementary efficacy demonstrated in MRSA-infected wounds and acute irradiation-impaired diabetic wounds.