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 Zn 2 ⁺-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. Graphical abstract