Transglutaminase‐Reinforced Hyaluronic Acid Bioadhesive with Calcium‐Polyphenol Synergy for Suture‐Free Wound Closure and Scar‐Reduced Healing

Abstract In order to address the fundamental drawbacks of conventional surgical sutures, such as infection susceptibility and scarring potential, an enzyme‐enhanced hyaluronic acid composite hydrogel (HANB‐MOF‐TG) is developed through a dual‐crosslinking strategy integrating tissue transglutaminase (TG) catalysis and calcium‐metal–organic frameworks (Ca‐MOFs) coordination. The bioadhesive system is engineered by encapsulating TGase within Ca‐MOFs, providing a sustained reductive environment to maintain enzymatic activity, followed by dynamic covalent crosslinking with nitrophenylboronic acid‐functionalized hyaluronic acid. This hierarchical design conferred exceptional tissue adhesion strength, broad‐spectrum antibacterial efficacy, and pro‐regenerative functionality. In a full‐thickness skin incision model in mice, the hydrogel enabled immediate wound closure compared to the blank group and achieved more precise wound edge alignment and improved healing outcomes relative to the suture and medical glue groups, owing to TG‐mediated collagen fiber alignment and extracellular matrix remodeling. Meanwhile, the hydrogel effectively inhibited scar formation, as evidenced by ≈30% reduction in α‐SMA expression at day 14 compared to day 7. Mechanistic studies revealed that the sustained release of Ca 2 ⁺ from MOF structures synergized with enzymatic crosslinking to activate fibroblast migration and angiogenesis. This work establishes a paradigm for next‐generation bioadhesives that unify mechanical robustness, biological functionality, and scarless healing in suture‐free wound management.