Mussel Inspired Hydrogel Promotes Axon Regeneration via Piezo1 Modulation and Cytoskeleton Dynamics in Synergy After Spinal Cord Injury

Abstract Paralysis resulting from spinal cord injury (SCI) arises from the limited regenerative capacity of axons. Mechanical factors have recently emerged as crucial regulators of axon regeneration, complementing or even surpassing chemical cues. In this study, we demonstrated that extracellular matrix stiffness, a key mechanical signal, not only modulated the regenerative capacity of neuronal axons in spinal cord with aging, but significantly fine‐tuned axon pathfinding through negative‐durotaxis pattern. So, it is imperative to develop a scaffold with biomimetic mechanical guidance properties to promote neural axon regeneration after SCI. Strikingly, inspired by the robust adhesive mechanism of mussels, we developed a facile strategy to synthesize catechol‐modified HAMA hydrogel (HAMA@CA) that mimics native spinal cord tissue properties, effectively modulates the biomechanical microenvironment, enhances tissue–implant adhesion, and ultimately promotes spinal cord integration after SCI. Mechanistically, HAMA@CA hydrogel regulates neuronal axon pathfinding following a negative durotaxis pattern, coinciding with changes in mechanosensitive signaling and actomyosin contractility via the Piezo1/RhoA/MLC pathway. RNA‐seq analysis also confirms mechanical‐mediated SCI repairing by HAMA@CA. These results demonstrates that HAMA@CA rationally combined with mechanical and biochemical cues create promising tissue‐engineered strategies to facilitate the repair of SCI. This innovative strategy holds significant promise for future clinical applications in the field.