A sequential stimuli-responsive hydrogel promotes structural and functional recovery of severe spinal cord injury.

Utilizing drug-loaded hydrogels to restore nerve conductivity emerges as a promising strategy in the treatment of spinal cord injury (SCI). However, many of these hydrogels fail to deliver drugs on demand according to the dynamic SCI pathological features, resulting in poor functional recovery. Inspired by the post-SCI microenvironments, here we report a time-sequential and controllable drug delivery strategy using an injectable hydrogel responsive to reactive oxygen species (ROS) and matrix metalloproteinases (MMPs). This strategy includes two steps: first, the hydrogel responds to ROS and releases nanodrugs to scavenge ROS, thereby mitigating inflammation and protecting neurons from oxidative stress in the initial SCI stages; second, the accumulation of MMPs triggers the release of vascular endothelial growth factor from nanodrugs to promote angiogenesis and neural stem cell differentiation in the late stage of SCI. In two clinically relevant SCI models, a single injection of the hydrogel led to an efficient structural and functional recovery of SCI 6 weeks after the intervention. We observed less inflammation, fibrosis, and cavities but more angiogenesis and neurons in the hydrogel-treated injured spinal cord region compared with the untreated animals. The hydrogel exhibits mechanical strength and conductivity comparable to natural spinal cord, facilitating its further clinical translation.