Zinc‐Directed Coordination Network Hydrogels for A20‐Mediated Inflammation Modulation and Enhanced Axonal Regeneration in Spinal Cord Injury

Abstract Remodeling the adaptive microenvironment with biomaterials presents a promising avenue for addressing chronic inflammation that contributes to spinal cord injury (SCI) repair. Hydrogels have been widely employed to enhance tissue regeneration following SCI. Additionally, zinc (Zn) ions are effective in immune modulation for the central nervous system. However, significant challenges remain in preparing hydrogels combining bioactive Zn²⁺ with biological functionality for traumatic SCI repair. In this study, a self‐healing hydrogel composed of an alginate network based on dynamic Zn²⁺/bisphosphonate (BP) cross–linking, and a silk fibroin interpenetrating polymer network is reported. It is observed that the neurite outgrowth is promoted by Zn²⁺ and shows dependency on Zn²⁺ concentration. Moreover, the Zn²⁺‐releasing hydrogel enhances neuronal axon growth and influences neural stem cell proliferation and differentiation. In addition, the hydrogel regulates microglial cell fate by upregulating the anti‐inflammatory signaling molecule A20 through inhibition of the NF‐κB pathway. Therefore, this hydrogel effectively improves immune response modulation while promoting neural regeneration and functional recovery, including motor, sensory, and bladder function in completely transected SCI. These results indicate the Zn²⁺/BP‐based hydrogel holds the potential for traumatic SCI treatment.