Diabetes is a highly prevalent disease worldwide, and the majority of patients with diabetes experience wound ulcers during the advanced stages of the disease.[1,2] Extensive bacterial infection, dysregulation of inflammation, the accumulation of reactive oxygen species (ROS), persistent vascular damage, and impaired tissue remodeling all complicate the healing of diabetic wounds.[3,4] The clinical care of diabetic wounds imposes a substantial burden on a country socially, and economically and significantly reduces patient quality of life. Existing conventional treatments cannot provide a satisfactory solution to the ulcer problems.[5,6] Many new therapies for wounds are being developed, including photothermal therapy, oxygen release therapy, nitric oxide generation therapy, wound dressings, and engineered stem cell-based therapies.[7] Among these, hydrogels with extracellular matrix-like structures have recently been developed and are widely used for repairing various skin defects. These hydrogels exhibit great potential in treating diabetic ulcers.[8], [9], [10], [11], [12] Therefore, a feasible approach for treating diabetic wounds is crucial for clinical practice.

Wound healing is a highly ordered process that involves hemostasis, inflammation, cell proliferation, and tissue remodeling.[13], [14], [15], [16], [17] However, the healing process in diabetic wounds is refractory and complex.[18,19] The combination of high glucose levels and dysimmunity compromised facilitates bacterial growth in moist skin wounds.[20] Therefore, eliminating bacteria is of utmost importance in diabetic wound management. Furthermore, the inflammatory phase is a fragile period in infected diabetic wounds, and anti-inflammation treatments at early stages are crucial for increasing the wound closure rate.[21] Subsequently, anti-inflammatory cells such as M2-type macrophages and pro-regenerative cells, proliferate rapidly and persistently to reduce inflammation and to reconstruct damaged tissue, respectively.[22] Current therapeutic strategies include antibiotic-based anti-infection approaches, nutritional supplementation via collagen derivatives, hyperbaric oxygen treatment, the promotion of angiogenesis via vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), and stem cell therapy.[23], [24], [25], [26], [27], [28], [29], [30] However, these single-function treatments are often costly and ineffective. Therefore, developing advanced wound dressings that match each step of wound repair and regeneration remains highly imperative.[4] New wound dressings should possess multiple functions, including high inherent antibacterial activity, ROS scavenging ability, anti-inflammatory capabilities, porous structures, and bioactive components for promoting cell adhesion, proliferation, angiogenesis, and tissue regeneration.

In this study, we engineered a hybrid multifunctional hydrogel assembled from synthetic glycopeptides to serve as a wound dressing to heal skin with bacterial infection. As shown in Figure 1, glucomannan (GM) was conjugated with an antimicrobial peptide (ILPWKWPWWPWRR) via dynamic imine bonds, denoted GM-AMP, to rapidly kill bacteria and provide a sterile environment for wounds. The DOPA4-G4-GRGDS peptide was conjugated to the backbone of GM to enable ROS scavenging, promote cell adhesion and spread, and exhibit anti-inflammatory properties. Additionally, the K(SL)3RG(SL)3KGKLTWQELYQLKYKGI peptide, which promotes angiogenesis, was conjugated to the backbone of GM. Three glycopeptides were physically mixed in water to form GM-Pgel with porous structures cross-linked by hierarchical fibers with diameters ranging from nanometers to micrometers. These hydrogels mediated macrophage polarization toward the M2 phenotype to suppress inflammation.[31] Furthermore, the hydrogel maintains a moist wound environment with no need for surgical removal because it is fully degradable. More importantly, GM is a polysaccharide composed of repeating mannose units that can specifically bind to MR ligands on macrophages, endowing hydrogels with the ability to mediate M2-type macrophage polarization. The amino acids and polysaccharide components of glycopeptides ensure their safety and degradability. Our results demonstrated that the multifunctional hydrogel GM-P significantly remodeled the microenvironment of injured tissues by eliminating bacterial infections, reducing inflammation by scavenging ROS, and polarizing macrophage toward the M2 phenotype, and promoting angiogenesis. The remodeling process expedites skin regeneration in full-thickness diabetic wounds infected with methicillin-resistant Staphylococcus aureus (MRSA). In conclusion, the multifunctional hybrid GM-P hydrogel holds great promise for clinical translation as a highly effective and nontoxic dressing that can eradicate microbes, scavenge ROS, and facilitate the healing of diabetic skin wounds.