Neuronal Dual-Specificity Phosphatase 26 Inhibition via Reactive-Oxygen-Species Responsive Mesoporous-Silica-Loaded Hydrogel for Spinal Cord Injury Repair.

Spinal cord injury (SCI) remains a formidable challenge in biomedical research, as the silencing of intrinsic regenerative signals in most spinal neurons results in an inability to reestablish neural circuits. In this study, we found that neurons with low axonal regeneration after SCI showed decreased extracellular signal-regulated kinase (ERK) phosphorylation levels. However, the expression of dual specificity phosphatase 26 (DUSP26)─which negatively regulates ERK phosphorylation─was reduced considerably in neurons undergoing spontaneous axonal regeneration. Therefore, we developed a system named F10@MS@UV-HG that integrated a DUSP26-specific inhibitor into reactive oxygen species-responsive nanoparticles and embedded them in photosensitive hydrogels. This system effectively downregulated DUSP26 expression in primary neurons and enhanced ERK phosphorylation, ultimately promoting axonal outgrowth. When transplanted into an SCI mouse model, the system achieved sustained drug release, specifically targeting the DUSP26/ERK/ELK1 pathway in the spinal neurons and facilitating short-term axonal regeneration. Additionally, long-term repair effects─including improved myelination and enhanced motor function─were evident in the SCI mice transplanted with F10@MS@UV-HG. The results suggested that activating ERK signaling by modulating DUSP26 expression in neurons after SCI could effectively promote axonal regeneration and functional recovery. Thus, the developed F10@MS@UV-HG system exhibits enormous potential as a therapeutic approach for patients with SCI.