<p>Full-thickness repair of chronic wounds poses significant clinical challenges. Although antioxidant and anti-inflammatory effects accelerate the healing of chronic wounds, achieving complete skin regeneration with appendages remains challenging in clinical practice. Herein, a unique selenium-containing thermo-sensitive hydrogel, poly(ethylene glycol)-<i>block</i>-poly(<i>L</i>-selenomethionine) (EG₄₅SeMet₂₅), is designed to reprogram the wound microenvironments and promote skin appendage regeneration in diabetic chronic wounds. EG₄₅SeMet₂₅ forms an injectable sol at room temperature and undergoes a sol-gel transition at body temperature, enabling complete filling of irregular wound defects. Moreover, EG₄₅SeMet₂₅ enhances cell proliferation and effectively scavenges intracellular reactive oxygen species (ROS), thereby exerting cytoprotective effects. Meanwhile, it modulates macrophage polarization to establish a pro-regenerative immune microenvironment. EG₄₅SeMet₂₅ significantly promotes the healing of full-thickness skin wounds in diabetic mice. After 14 d, the remaining unhealed wound area decreases to 2.53% of that in the Control group, accompanied by accelerated angiogenesis and a significant increase in skin appendage formation. In summary, EG₄₅SeMet₂₅ is a promising antioxidant organic selenium hydrogel that not only interrupts the “ROS-inflammation” cycle but also enables functional full-thickness skin repair, offering a unique strategy for treating chronic wounds.</p>