Multi‐Modal Therapy for Diabetic Ulcers: A Hydrogel Platform Combining Antibacterial, Oxygenating, ROS‐Scavenging, and Pro‐Healing Functions

Abstract Diabetic ulcers, characterized by excessive accumulation of reactive oxygen species (ROS), local hypoxia, persistent inflammation, and secondary bacterial infection, pose a serious threat to human health. To address these challenges, this study developed an injectable hydrogel based on covalent cross‐linking between polyethylene glycol derivatives and ε‐polylysine. This hydrogel is further loaded with recombinant Milk fat globule‐epidermal growth factor‐VIII (rMFG‐E8) and ferulic acid (FA)‐loaded mesoporous manganese dioxide (HM‐FA), forming a “single application, multiple benefits” platform. The hydrogel effectively inhibited planktonic bacteria and controlled wound infection owing to the inherent antibacterial activity of ε‐polylysine. Under the acidic microenvironment of diabetic ulcers, the hydrogel gradually degraded and released HM‐FA, which scavenged excess ROS and continuously generated oxygen via, thereby alleviating local hypoxia and oxidative stress and reducing inflammatory responses. Subsequently, FA released from the further disintegration of HM‐FA acted synergistically with rMFG‐E8 to activate the PI3K/Akt signaling pathway, promoting angiogenesis and tissue regeneration. In vivo experiments demonstrated that the hydrogel exhibited good biocompatibility, significantly suppressed inflammatory responses, and accelerated wound closure in a diabetic ulcer mouse model. In summary, the integrated treatment strategy proposed in this study significantly simplifies clinical procedures and shows promising potential for translational application in diabetic ulcer therapy.