Adhesive hydrogels containing quaternary ammonium salt (QAS) moieties have shown attractive advantages in treatment for acute wounds, attributed to their high performances in wound sealing and sterilization. However, the introduction of QAS commonly leads to high cytotoxicity and adhesive deterioration. Here, aimed to solve these two issues, a self-adaptive dressing with delicate spatiotemporal responsiveness is developed by employing cellulose sulfate (CS) as dynamic layers to coat QAS-based hydrogel. In detail, due to the acid environment of wound in the early stages of healing, the CS coating will quickly detach to expose the active QAS groups for maximum disinfectant efficacy; meanwhile, as the wound gradually heals and recovers to a neutral pH, the CS will remain stable to keep QAS screened, realizing a high cell growth-promoting activity for epithelium regeneration. Additionally, attributed to the synergy of temporary hydrophobicity by CS and slow water absorption kinetics of the hydrogel, the resultant dressing possesses outstanding wound sealing and hemostasis performance. At last, w e anticipate this approach to intelligent wound dressings based on dynamic and responsive intermolecular interaction can also be applied to a wide range of self-adaptive biomedical materials employing different chemistries for applications in medical therapy and health monitoring. This article is protected by copyright. All rights reserved.