A dual-action nanoparticle approach for spinal cord injury treatment: ferroptosis inhibition, inflammation control, and Myelin preservation.

Abstract

Spinal cord injury (SCI) initiates secondary injury cascades, including ferroptosis and neuroinflammation, which contribute to progressive neuronal and myelin loss. Single-cell RNA sequencing defines a therapeutically actionable window for selenium (Se) replenishment: neuronal and oligodendrocyte selenoproteins-especially Gpx4-show a transient rise at 1-day post-injury followed by sustained suppression with induction of ferroptosis drivers, indicating Se-limited antioxidant collapse. In this study, we extracted a novel Polygonatum-derived fructan and, for the first time, used it to coat selenium nanoparticles, synthesizing PRP@SeNPs via a green, ascorbate-mediated reduction. The PRP coating yields smaller hydrodynamic size, a more negative zeta potential, and a front-loaded yet sustained Se-release profile that aligns with the scRNA-seq-identified supplementation window. In vitro, PRP@SeNPs restore Gpx4 expression, reduce lipid peroxidation, scavenge ROS, and promote M2 microglial polarization. In situ administration in a T-cut SCI mouse model suppresses ferroptosis and glial activation, preserves neuronal and myelin integrity, enhances axonal regeneration, and improves motor function (Basso Mouse Scale, gait analysis, electrophysiology). PRP@SeNPs thus provide a drug-free, biocompatible nanotherapeutic strategy to replenish Se, mitigate secondary injury mechanisms, and promote neuroprotection and remyelination for advanced functional recovery after SCI.