Injectable Metal-Free Carbon Dot-Integrated Hydrogel for Regulating Inflammation via Macrophage Metabolic Reprograming in Spinal Cord Injury Therapy

Excessive oxidative stress following spinal cord injury (SCI) provokes a heightened pro-inflammatory reaction, which severely obstructs nerve regeneration and functional restoration. While antioxidant nanozymes that eliminate reactive oxygen species (ROS) and attenuate inflammatory cascades show promise for SCI therapy, the potential neurotoxicity associated with metal ions in most current nanozymes limits their clinical translation. This study demonstrates a strategy based on metal-free carbon dots (D-CDs) that effectively eliminates ROS and reprograms macrophage metabolism via the P53 signaling pathway activation, thereby steering their polarization toward a pro-regenetive phenotype. Furthermore, an injectable chitosan-based dynamic hydrogel (QP hydrogel) is developed to enable sustained local delivery of D-CDs at the injury site, maintaining effective therapeutic concentrations and enhancing clinical feasibility. In vitro experiments confirmed that the D-CDs@QP hydrogel effectively promoted macrophage M2-polarization and enhanced neurogenesis from neural stem cell populations, while suppressing astrocytic differentiation. In a mouse model of complete SCI, D-CDs@QP significantly enhanced the restoration of both motor and bladder functions. This study develops a metal-free carbon nanozyme-integrated hydrogel system that reprograms macrophage mitochondrial metabolism, offering a effective strategy to combat neuroinflammation, stimulate neuroregeneration, and promote functional recovery post-SCI.