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

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.