The skin serves as a protective barrier for the body, shielding it from harmful substances such as bacteria, viruses, and environmental toxins (Kang et al., 2016). In the past few years, wound healing has emerged as a significant clinical obstacle, leading to substantial financial strain on a global scale. Due to the intricate nature of wound healing and the occurrence of severe wounds, it is necessary to develop comprehensive healing strategies that can address all stages of the wound healing process, including inflammation, proliferation, and remodelling. Wounds often become stuck at the inflammation stage due to the presence of hyperglycemia and an imbalanced redox system (Guan et al., 2021). This imbalance can lead to an overproduction of reactive oxygen species (ROS) and pro-inflammatory cytokines, further complicating the healing process (Zhao et al., 2022). Traditional wound dressings such as bandages, gauzes and foam sponges play a crucial role in the healing process by providing a protective barrier against external contaminants and promoting an optimal environment for tissue regeneration (Dong and Guo, 2021). However, these conventional dressings may not fully meet the diverse demands of the complicated healing process. Due to their abundant water content, extensive porosity and tissue-like characteristics, hydrogels display significant potential in the field of wound care by creating a physical barrier and maintaining a favorable moist environment for regeneration and epithelialization (Manzari et al., 2021). Hydrogels have played an important role in assisting healing processes over the years. However, more effective and biologically functional dressing options in biomaterials and biomedical engineering are urgently needed to better meet the complex demands of the wound microenvironment. (See Scheme 1.).

During the initial stages in the wound healing process, infected wounds typically become more acidic (pH 4.5–6.5) due to the presence of bacterial byproducts and the production of pus. As foreign objects are eliminated and the wound progresses into the proliferative phase, its pH gradually increases, temporarily becoming more alkaline (pH 7–8) (Wu et al., 2022). Copper ions cross-linked polymer chains usually offer the potential for achieving a more even distribution of copper throughout the biomaterial. This uniform distribution can lead to enhanced coordination effects between Cu2+ and the polymer, allowing for greater control over the release of Cu2+ in response to specific pH environments within wound beds. For antibacterial activity, the ideal Cu2+ concentration ranges from approximately 0.64 to 6.4 μg mL-1 (Tran et al., 2017), while for angiogenic activity, the ideal Cu2+ concentration is much lower, ranging from 0.05 to 0.36 μg mL-1 (Gérard et al., 2010). This difference in required concentrations of Cu2+ highlights the specific and targeted nature of copper on different biological processes within the body. As a result, a hydrogel with pH-responsive copper cross-linking properties, which can release copper ions as needed, could enhance bacterial elimination during the infection phase and support angiogenesis during the proliferation phase. The antibacterial effects of copper ions occur through different mechanisms, such as penetrating the outer membrane of bacteria by destroying the cell membrane through electrostatic adsorption and interfering with key metabolic pathways and enzyme activity for bacterial survival (xxx, 2018). In addition, copper ions also play a crucial role in promoting angiogenesis by regulating the gene expression related to angiogenesis and adjusting ROS levels. However, an excess amount of copper supplements during the process of angiogenesis may cause oxidative stress within cells. It is crucial to carefully regulate the delivery of copper ions to wound beds for effectively promoting bacterial removal and neovascularization without harming surrounding tissues. Thus, precise and stage-adaptive delivery of copper ions plays a significant role in promoting wound healing and tissue regeneration.

Excessive production of ROS can cause oxidative stress, leading to damage to surrounding tissues, exacerbating inflammatory storms and impairing wound healing (Xiong et al., 2023). Wound healing can be effectively promoted by clearing ROS and regulating the expression of inflammatory factors. Polyphenols are important natural antioxidants, such as protocatechuic acid, a phenolic acid that occurs naturally in many vegetables and fruits and has antioxidant, anti-inflammatory and antibacterial effects (Guo et al., 2021). Polyphenol molecules contain many phenolic hydroxyl groups, which can form stable complexes with metal ions under certain conditions. Polyphenol-metal nanocomposites represent a novel form of enzyme mimicry, possessing exceptional characteristics and extensive potential applications that are not found in natural enzymes. In addition, polyphenol-metal nanocomposites exhibit diverse catalytic capabilities and can function as enzyme analogs, including oxidases, peroxidases, reductases, etc. (Xu et al., 2023). Their catalytic performance and selectivity surpass those of natural enzymes, facilitating efficient catalytic processes. The SOD-CAT cascade works by combining the functions of the superoxide dismutase (SOD) and catalase (CAT) reactions. Firstly, the SOD reaction process transforms superoxide (O2•−) to hydrogen peroxide (H2O2), and then, the CAT reaction process further catalyses H2O2 to produce water (H2O) and oxygen (O2) (Kim et al., 2024). This sequential catalytic process allows for the effective elimination of ROS and has potential applications in biomedical research and disease treatment.

Herein, we present a straightforward approach to produce enzyme-like GCP hydrogels by combining GA, Cu2+, and PA in a one-step assembly process. The GCP hydrogels showed on-demand release of copper ions at different stages of wound healing. In the early infection stage, Cu2+ was released quickly under acidic pH conditions, but the release rate was reduced at neutral pH, which helps to provide antibacterial effects during the early infection stage and promotes angiogenesis in the later proliferation stage. In addition, the phenolic hydroxyl group in PA functions as both a reducing agent and protective ligand by binding with Cu2+ to form the catalytic centre. This contributed to its SOD-CAT-like cascade catalytic performance and provided remarkable antioxidant and anti-inflammatory effects. Moreover, GA in GCP hydrogels has excellent immunomodulatory properties and induces the polarization of M2 macrophages, thereby reducing the inflammatory response and regulating the wound microenvironment. Meanwhile, the hydrogel effectively prevented the formation of bacterial biofilms, eradicated existing biofilms, and enhanced the healing rate of wounds in mice infected with MRSA. This research highlights the impressive ability of the multifunctional GCP hydrogel to adapt to multistage microenvironments and on-demand release ability to promote wound healing, making it a promising and highly efficient platform for regenerating complicated wound tissues.