EGR1‐Driven Re‐Epithelialization Enabled by Rutin‐Based Self‐Assembled Hydrogel Platform for Oral Ulcer Therapy

Abstract Oral ulcer (OU) is a highly prevalent mucosal disease characterized by persistent epithelial disruption. The primary challenge in its prolonged healing process is the disorder of re‐epithelialization. This study develops a self‐assembled hydrogel platform based on the natural small molecule rutin, which overcomes the re‐epithelialization barrier through the synergistic effects of early growth response factor 1 (EGR1) gene programming and microenvironment remodeling. In this hydrogel, rutin formed supramolecular structures via hydrogen bonds and π–π interactions without structural modification. In vitro experiments confirm that rutin‐based self‐assembled hydrogel (RUTG) possesses excellent sustained‐release properties and biocompatibility. Moreover, RUTG specifically regulates the transcriptional activation and translation of EGR1, thereby mediating the expression of re‐epithelialization‐related protein SOX9, and ultimately accelerating cell proliferation and migration as well as promoting re‐epithelialization. Additionally, RUTG demonstrates beneficial anti‐inflammatory and antioxidant properties, effectively remodeling the local microenvironment. In vivo studies using an oral ulcer model further confirm that RUTG could significantly accelerate the re‐epithelialization process, shorten the ulcer healing cycle, and achieve functional tissue reconstruction. Collectively, this carrier‐free hydrogel system, which integrates gene programming with microenvironment modulation to achieve efficient re‐epithelialization, holds promise for introducing novel approaches to the treatment of oral ulcers.