Spinal cord injury (SCI) remains a challenging clinical problem worldwide, due to the lack of effective drugs for precise treatment. Among the complex pathophysiological events following SCI,
reactive oxygen species (ROS) overproduction plays a particularly significant role. As therapeutic agents for neurological diseases,
tetramethylpyrazine (
TMP) and monosialotetrahexosylganglioside (GM1) have been widely used in the clinical treatment of SCI. Our previous studies have reported that functionalized
selenium nanoparticles (SeNPs) exhibit excellent
antioxidant activity against oxidative stress-related diseases. Therefore, in this study, novel multifunctionalized SeNPs decorated with
polysaccharide-
protein complex (PTW)/PG-6
peptide and loaded with
TMP/GM1 were rationally designed and synthesized, which exhibited a satisfactory size distribution and superior stability. Furthermore, the protective effects of SeNPs@GM1/
TMP on PC12 cells against
tert-butyl hydroperoxide (t-BOOH)-induced cytotoxicity and the underlying mechanisms were also explored. Flow cytometric analysis indicated that SeNPs@GM1/
TMP showed strongly protective effects against t-BOOH-induced G2/M phase arrest and apoptosis. Moreover, we found that SeNPs@GM1/
TMP could attenuate ROS overproduction to prevent
mitochondria dysfunction via inhibiting the activation of p53 and MAPK pathways. Effects of SeNPs@GM1/
TMP on functional recovery after SCI were evaluated by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. The results of
hematoxylin-
eosin staining and Nissl staining also showed that SeNPs@GM1/
TMP provided a
neuroprotective effect in SCI rats. This finding suggests that SeNPs@GM1/
TMP could be further developed as a promising nanomedicine for efficient SCI treatment.