An integrated hydrogel-V3 interneuron therapy promotes functional repair of spinal cord injury via neural circuit reconstruction and microenvironment remodeling

Spinal cord injury (SCI) disrupts neural circuits and creates an inhibitory microenvironment, posing challenges such as low cell survival rates and limited host integration for traditional cell transplantation therapies. This study developed an injectable, self-adaptive, and self-repairing oxidized hyaluronic acid-carboxymethyl chitosan (OHA-CMCS) dual-network interpenetrating hydrogel. This hydrogel serves as a functionalized, dynamically responsive cell-matrix co-delivery platform for delivering spinal cord-specific V3 neuronal precursors derived from human pluripotent stem cells. Through tissue-mimetic mechanical design, the hydrogel closely simulates the spinal cord tissue microenvironment. Its reversibly crosslinked network exhibits excellent compliance and self-healing capabilities, forming bidirectional feedback coupling with V3 cells across mechanical and biochemical dimensions, thereby significantly enhancing cell survival and functional maturation. In rats with complete spinal cord transection, the "material-cell synergistic system" (OC0.33+V3) formed by the OHA-CMCS hydrogel and V3 cells markedly improved motor function (BBB score, grip strength, gait analysis) and remodeled the injured microenvironment. Mechanistic studies reveal that this system drives microenvironmental reprogramming through material-cell interactions, inhibiting glial scar formation, inducing M2 polarization of microglia, and promoting axonal regeneration and vascular remodeling. Chemogenetic validation further confirms that transplanted V3 neurons successfully integrate into host neural circuits and exert inhibitory regulatory functions. This study proposes a dual-engine strategy of "material-driven regulation and cell-function integration," revealing the mechanism by which biomimetic hydrogels synergize with neurons to repair spinal cord injury, establishing a new paradigm for intelligent neuroregeneration systems.