A nasally delivered ferroptosis nano-inhibitor for spinal cord injury repair.

Spinal cord injury (SCI) triggers a cascade of secondary damage in which ferroptosis, an iron-dependent form of lipid peroxidation, plays a pivotal role. Early intervention is essential, yet clinical delays and limited central nervous system (CNS) penetration of conventional agents restrict therapeutic efficacy. Here, we developed a pH-responsive cerium-doped mesoporous silica nanoplatform (CeMSN) loaded with Vitamin K (VK). Following intranasal administration, CeMSN-associated fluorescence rapidly appeared in the CNS and preferentially localized at the injured spinal cord within 3 h, consistent with extracellular/perineural entry along olfactory- and trigeminal-associated pathways, followed by distribution through interconnected cerebrospinal fluid, interstitial, and perivascular compartments. In the acidic post-injury microenvironment, CeMSN underwent pH-responsive degradation, which is expected to facilitate local VK release and subsequent activation of the FSP1 pathway, while Ce3+/Ce4+ redox cycling mimicked superoxide dismutase and catalase activities to scavenge reactive oxygen species. This dual mechanism restored redox homeostasis, alleviated iron overload, and stabilized mitochondrial function. In a murine SCI model, CeMSN@VK significantly promoted axonal preservation, remyelination, and functional recovery, supporting its potential as a rapid, minimally invasive ferroptosis-targeting therapy. This strategy may offer a clinically feasible solution for early neuroprotection in SCI and related CNS disorders.