A Blood‐Derived Double‐Network Hydrogel with Robust Wet Adhesion for Keratinized Mucosa Regeneration via Neutrophil Phenotype Reprogramming and Mechanophysical Niche Modulation

ABSTRACT Reconstruction of keratinized mucosa (KM) with sufficient dimensions is critical for long‐term periodontal and peri‐implant health. However, existing biomaterials struggle to recapitulate the complex biophysical and biochemical microenvironment of KM while achieving stable adhesion and integration in the wet and mechanically dynamic oral cavity. Here, we design a photocrosslinkable double‐network hydrogel composed of methacrylated platelet‐rich fibrin (iPRF‐MA), N‐hydroxysuccinimide‐functionalized alginate (Alg‐NHS), and luteolin‐loaded epigallocatechin gallate microspheres (Lut@EGCG) to enable KM regeneration in the challenging oral environment through dual microenvironmental modulation. At the material level, the covalent network from iPRF‐MA and the supramolecular network based on Alg‐NHS work synergistically, resulting in strong wet tissue adhesion and high fatigue resistance, which collectively prevent hydrogel dislodgement under oral dynamic stresses. Biochemically, the hydrogel enables sustained release of growth factors and EGCG, synergistically enhancing angiogenesis and immune regulation, while also redirecting neutrophil phenotype toward a phagocytic state for specific antibacterial activity. Biophysically, the hydrogel provides gingival fibroblasts with a mechanically instructive microenvironment that activates mechanotransduction signaling and accelerates extracellular matrix remodeling. In vivo experiments confirm outstanding KM regeneration following treatment with the double‐network hydrogel. This study demonstrates a microenvironment‐targeting strategy for KM reconstruction through rational hydrogel design, offering a therapeutic platform for functional KM regeneration.