Multifunctional Hydrogel with Mild Photothermal Properties Enhances Diabetic Wound Repair by Targeting MRSA Energy Metabolism

Background Diabetic wound infections, exacerbated by multidrug-resistant pathogens like MRSA, remain a critical challenge due to biofilm persistence and dysregulated oxidative-inflammatory-metabolic crosstalk. Results In this work, we engineered COG-Z@P200 hydrogel, a chitosan-based hydrogel integrating polydopamine-coated ZIF-8 nanoparticles, to synergize mild photothermal therapy (40–45°C) with metabolic-immune reprogramming. Upon NIR irradiation, COG-Z@P200 disrupted MRSA through Zn²⁺-mediated membrane destabilization and localized hyperthermia, achieving >99.5% eradication via combined physical puncture and metabolic interference. Multi-omics analyses revealed suppression of glycolysis (eno, gap downregulation), TCA cycle arrested (s ucC, sdhA, icd inhibition), and disruption of arginine biosynthesis (arcA, arcC, arcD downregulation), impairing biofilm formation and pathogenicity. Concurrent silencing of quorum sensing and virulence genes ( agr, sec, lac, opp, sdrD ) further destabilized MRSA, while upregulation of stress-response genes ( yidD, nfsA, kdpA ) indicated bacterial metabolic paralysis. In diabetic murine models, the hydrogel attenuated oxidative stress (DHE-confirmed ROS reduction), polarized macrophages to pro-healing M2 phenotypes (Arg-1⁺/TNF-α↓), and enhanced angiogenesis (VEGF/CD31↑) alongside aligned collagen deposition. This multifunctional action accelerated wound closure by 48% versus controls, outperforming clinical standards. By converging nanomaterial-enabled bactericidal strategies with host microenvironment recalibration, COG-Z@P200 hydrogel redefined diabetic wound management, offering an antibiotic-free solution against multidrug-resistant infections. Conclusion Our work established a biomaterial paradigm that concurrently targets pathogen vulnerabilities and restores tissue homeostasis, addressing the multidimensional complexity of chronic wounds.