Reactive oxygen species-responsive hydrogel accelerates diabetic wound repair by modulating endoplasmic reticulum stress

Diabetic wounds exhibit persistent inflammation and endoplasmic reticulum (ER) stress (ERS) in high-glucose environments, leading to cellular dysfunction and limited tissue regeneration, which poses a significant challenge for clinical treatment. In this study, we developed a reactive oxygen species (ROS)-responsive hydrogel (HPA@A&T) that promotes the healing of diabetic wounds by restoring cellular homeostasis through the mitigation of the ERS. The hydrogel consists of polyvinyl alcohol and hyaluronic acid-grafted 3-amino phenylboronic acid, which rapidly forms a gel via a phenylboronate bond that can be severed at high-ROS levels to achieve targeted degradation and drug release. The hydrogel encapsulates both the astaxanthin-zinc ion complex and tauroursodeoxycholic acid, which act synergistically to downregulate the expression of the unfolded protein response core proteins protein kinase RNA-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor-4 (ATF4), and C/EBP homologous protein (CHOP), thereby contributing to the restoration of ER homeostasis and cellular function. HPA@A&T hydrogels have demonstrated biocompatibility in both cellular and animal studies, enhancing cellular activity and promoting wound healing. In conclusion, HPA@A&T hydrogels can be triggered by ROS to release drugs, effectively regulate cellular ERS levels, and maintain cellular homeostasis through the PERK-eIF2α-ATF4-CHOP pathway, providing a novel smart response strategy for the treatment of diabetic wounds.