Dual‐Network Protein Hydrogels Promote Rapid Hemostasis and Immune‐Regulated Scarless Tissue Regeneration

ABSTRACT Bioadhesive hydrogels hold great promise for rapid hemostasis and tissue repair, yet their clinical translation remains limited by inadequate mechanical robustness, transient adhesion, and uncontrolled fibrotic healing, which can cause pain, prolong wound healing, and unsightly scars. Here, we report an injectable, dual‐network fibrin–dextran hydrogel that integrates the intrinsic bioactivity of fibrin with the mechanical tunability of methacrylated dextran (Dex‐MA) and the strong adhesion to wet, slippery wound skin mediated by dopamine methacrylamide (DMA). The hydrogel undergoes dual enzymatic and redox‐triggered crosslinking—via thrombin and dithiothreitol to form an adaptive network exhibiting programmable stiffness and dynamic adhesion. Beyond its rapid hemostatic function, the hydrogel demonstrates potent anti‐inflammatory and anti‐scar formation activity, achieved through reactive oxygen species (ROS) scavenging and macrophage polarization toward a pro‐regenerative M2 phenotype. Transcriptomic analysis (RNA‐seq) further reveals activation of antioxidant defense and suppression of TGF‐β‐driven fibrotic pathways, thereby minimizing collagen hyper‐deposition and scar tissue formation. In rat liver and tail amputation models, the hydrogel significantly reduced blood loss, shortened bleeding time, and promoted scar‐free wound closure. This study establishes a bioinspired hydrogel platform that integrates hemostasis, immunomodulation, and anti‐fibrotic healing, offering a generalized and sustainable strategy for designing next‐generation bioadhesive materials for scarless tissue regeneration.