Dual‐Responsive Multi‐Functional Silica Nanoparticles With Repaired Mitochondrial Functions for Efficient Alleviation of Spinal Cord Injury

Preserved/rescued mitochondrial functions have a significant effect on maintaining neurogenesis, axonal carriage, and synaptic plasticity following spinal cord injury (SCI). We fabricated an ingenious redox-responsive strategy for commanded liberation of NADH (reduced form of nicotinamide-adenine dinucleotide) by bioactive diselenide-containing biodegradable mesoporous silica nanoparticles (<b>Se@NADH</b>). The nanocarrier-embedded NADH can be liberated in a controlled pattern through the cleavage of diselenide bonds in the presence of reactive oxygen species (ROS) or glutathione (GSH). The NAD⁺ was regenerated by the reactions between released NADH and harmful ROS to antagonize mitochondrial dysfunction and increase ATP synthesis, promoting axon regeneration across SCI areas. This nanosystem increased the stability of NADH during prolonged blood circulation time, reduced the clearance rate, exhibited significant anti-inflammatory as well as neuroprotective effects and enhanced the regeneration of electrophysiological conduction capacity across SCI areas. Importantly, <b>Se@NADH</b> suppressed glial scar formation and promoted neuronal generation as well as stretching of long axons throughout the glial scar, thereby improving actual restoration of locomotor functions in mice with SCI and exerting ascendant therapeutic effects. Targeting of mitochondrial dysfunction is a potential approach for SCI treatment and may be applied to other central nervous system diseases.