Selenium‐Containing Polyurethane Thermo‐Sensitive Hydrogel Accelerates Diabetic Wound Healing by Activating Unfolded Protein Response

ABSTRACT Diabetic wound healing impairment, a common complication of diabetes, has limited clinical treatment options and poor therapeutic outcomes, causing significant physical pain and psychological burden for patients. This study aims to accelerate wound healing by modulating cellular stress responses, offering a safe and efficient new therapeutic strategy. Herein, a selenium‐containing polyurethane (SePU) thermo‐sensitive hydrogel was synthesized, and its mechanism for promoting diabetic wound healing by activating the unfolded protein response (UPR) was elucidated. Hydroxybutyl chitosan (HBC) offers a more convenient application for SePU, with its high hydroxybutyl substitution enabling the hydrogel to undergo a rapid sol–gel transition at physiological temperatures. In vitro experiments showed that SePU thermo‐sensitive hydrogel (SePU/HBC), at appropriate concentrations, significantly promoted the proliferation, spreading, migration, and adhesion of human skin fibroblasts (HSFs), while inhibiting inflammation. In vivo diabetic mouse model, SePU/HBC exhibited a significant wound‐healing effect, promoting re‐epithelialization, collagen formation and maturation. Mechanistic studies revealed that SePU/HBC alleviated endoplasmic reticulum stress under hyperglycemic conditions by activating the UPR‐related gene ATF6 to alleviate endoplasmic reticulum stress (ERS) and inhibit apoptosis. This study offers a novel strategy for diabetic wound treatment using SePU/HBC, which activates the UPR and inhibits apoptosis, demonstrating promising clinical applications for wound healing.