Spatiotemporal Delivery of Required Facilitators for Microenvironment Remodeling Propels Neural Regeneration after Spinal Cord Injury

Abstract Intricate pathological responses and multiple components within the lesion make it challenging to repair spinal cord injury (SCI). A multifunctional hybrid neural restorative conduit is developed, composed of a sandwich‐like hydrogel encapsulated within a polycaprolactone (PCL) nanofiber membrane. The sandwich structure consists of a hyaluronic acid‐graft‐dopamine (HADA)/HGF‐(RADA)4‐DGDRGDS (HRR) hydrogel loaded with epidermal growth factor (EGF), neurotrophin 3 (NT3), and glial‐derived neurotrophic factor (GDNF), flanked by gelatin methacryloyl (GelMA) hydrogels containing catalase at both ends. The hybrid conduit enables the spatiotemporal release of multiple bioactive factors, precisely targeting critical pathological cascades after SCI. This approach reduces oxidative stress, promotes neuronal survival at the lesion borders, facilitates the relay of ascending and descending axons, and enhances signal transmission across the lesion. Restored serotonergic signaling enhances motor neuron excitability, facilitating functional recovery, while reconstitution of bladder reflexes improves urinary control. By orchestrating the reinstatement of multiple essential mechanisms to counteract the pathological progression of the hostile post‐SCI microenvironment, this approach provides a strategy for regenerative therapies targeting SCI.