Synergistic Photothermal and Cuproptosis-like Death Dual-Therapeutic Copper-Phenolic Hydrogel for Infected Wound Healing

Abstract Background Chronic wound healing remains challenging due to persistent inflammation, especially caused by methicillin-resistant Staphylococcus aureus (MRSA) and hindered tissue regeneration. Methods To resolve this issue, we developed a multifunctional hydrogel (CMCS/PA@Cu) via Schiff base and metal coordination bonds crosslinking between carboxymethyl chitosan (CMCS) and protocatechualdehyde-copper complexes (PA@Cu). The hydrogel can combine the delivery of copper ions (Cu2+) with photothermal therapy. Meanwhile, it endows the material with remarkable self-repairing properties, injectability, and sufficient tissue adhesion, thereby overcoming the limitations of CMCS hydrogels. Results More importantly, when exposed to 808 nm NIR irradiation (0.77 W/cm2), the instantaneous local temperature (47°C) synergistically interacts with Cu2+-triggered cuproptosis-like death. Transcriptomic data show that the excessive Cu2+ accumulation damages the tricarboxylic acid (TCA) cycle as well as respiratory chain of the bacteria, leading to metabolic breakdown and energy exhaustion, thereby effectively avoiding antibiotic resistance. In addition to direct antibacterial effect, the CMCS/PA@Cu hydrogel also actively reshapes the immune microenvironment of host wound. At the mechanism level, the hydrogel causes macrophages to transform into the pro-repair M2 phenotype. The phenotypic change is accompanied by the simultaneous upregulation of transcriptional programs that regulate glycolysis and oxidative metabolism. Moreover, the hydrogel can stimulate angiogenesis and enhance collagen synthesis. In vivo, this hydrogel markedly accelerates the closure of MRSA-infected wounds, reduces inflammation, and promotes orderly tissue regeneration. Conclusions Overall, this interlinked system offers a remarkable non-antibiotic strategy that enables spatially and temporally controllable treatment for complex wound care.