Self‐Enhancing Drug Pair‐Driven Selenium Nanotherapeutics Reverses Microglial Pyroptosis Through NLRP3/Caspase‐1 Pathway and Neuronal Apoptosis for Treatment of Spinal Cord Injury

Abstract Spinal cord injury (SCI) constitutes a critical occurrence that results in the disruption of both motor and sensory functions. Oxidative stress‐induced apoptosis and pyroptosis have been identified as critical contributors to neuronal damage during the secondary injury phase following SCI. Therefore, this study focuses on the development of self‐enhancing drug pair‐driven selenium (Se) nanotherapeutics, loading with 2,3,5,6‐tetramethylpyrazine (TMP) and Ginsenoside Rg1 (Rg1), to enhance the treatment of SCI. The engineered LET/TMP/Rg1@Se NPs exhibits remarkable antioxidant properties, effectively reducing oxidative stress‐induced neuronal injury by minimizing reactive oxygen species (ROS) accumulation and restoring mitochondrial function. In addition to their antioxidant effects, this nanotherapeutics demonstrates significant anti‐pyroptotic effects in BV2 microglial cells by modulating the NLRP3/caspase‐1 pathway, leading to the decreased release of pro‐inflammatory cytokines IL‐1β and IL‐18. Moreover, this inhibition of inflammatory cascade response diminishes the neuroinflammation‐induced neuronal apoptosis and promotes axonal regeneration of neurons in vitro. In a mouse model of SCI, treatment with LET/TMP/Rg1@Se NPs results in improved motor function and axonal regeneration, attributed to the inhibition of apoptosis and pyroptosis, highlighting the scientific basis for the synergistic self‐enhancing effect of drug pair‐driven Se nanotherapeutics as an innovative strategy for effective SCI therapy.