Seleno‐Amino Acid Nanotherapeutics Upregulates Selenoproteins to Inhibit Oxidation and Neuroinflammation for Spinal Cord Injury Recovery

ABSTRACT Spinal cord injury (SCI) is a neurological disorder, with neuronal oxidative and inflammatory damage being the key pathogenic mechanisms. The essential trace element selenium (Se) exerts anti‐inflammatory and anti‐oxidant neuroprotective effects primarily by regulating selenoproteins, demonstrating great potential in SCI neuroprotective therapy. Herein, we found that the damage of spinal cord tissue leads to acute‐phase depletion of endogenous selenoprotein, and Se supplementation, especially selenomethionine (SeM), can exert a neuroprotective effect. We further developed a lipid nanoparticles (LNP) encapsulation system for SeM delivery (SeM@LNP) to enhance its blood circulation time and biological utilization rate, thereby facilitating its penetration through the blood‐spinal cord barrier (BSCB) and accumulation in the spinal cord. SeM@LNP effectively scavenges glucose‐oxygen deprivation (OGD)‐induced excessive reactive oxygen species (ROS) accumulation in neurons via upregulating the expression of antioxidative selenoproteins, thereby regulating mitochondrial fission and fusion by activating the AMPK‐MFN1/OPA1‐Drp1 axis to maintain mitochondrial morphology, function and energy metabolism. Furthermore, SeM@LNP suppresses microglia activation and reduces pro‐inflammatory factor levels to mitigate neuroinflammation, then exhibits synergistic anti‐oxidant and anti‐inflammatory activity in vivo, effectively alleviating nervous impairment. These findings highlight SeM@LNP as a potential nanotherapeutic platform for SCI, and elucidate its dual anti‐inflammatory and antioxidant mechanisms in mitigating secondary damage cascades post‐SCI.