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.