Nitric Oxide-Releasing Mesoporous Hollow Cerium Oxide Nanozyme-Based Hydrogel Synergizes with Neural Stem Cell for Spinal Cord Injury Repair

Neural stem cell (NSCs) transplantation is a promising therapeutic strategy for spinal cord injury (SCI), but its efficacy is greatly limited by the local inhibitory microenvironment. In this study, based on l-arginine (l-Arg)-loaded mesoporous hollow cerium oxide (AhCeO2) nanospheres, we constructed an injectable composite hydrogel (AhCeO2-Gel) with microenvironment modulation capability. AhCeO2-Gel protected NSCs from oxidative damage by eliminating excess reactive oxygen species while continuously delivering Nitric Oxide to the lesion of SCI in a pathological microenvironment, the latter of which effectively promoted the neural differentiation of NSCs. The process was confirmed to be closely related to the up-regulation of the cAMP-PKA pathway after NO-induced calcium ion influx. In addition, AhCeO2-Gel significantly promoted the polarization of microglia toward the M2 subtype as well as enhanced the regeneration of spinal nerves and myelinated axons. The prepared bioactive hydrogel system also efficiently facilitated the integration of transplanted NSCs with host neural circuits, replenished damaged neurons, alleviated neuroinflammation, and inhibited glial scar formation, thus significantly accelerating the recovery of motor function in SCI rats. Therefore, AhCeO2-Gel synergized with NSCs transplantation has great potential as an integrated therapeutic strategy to treat SCI by comprehensively reversing the inhibitory microenvironment.