Diselenide-bridged mesoporous silica nanoplatform for baicalin delivery facilitates spinal cord injury repair via CHCHD2-mediated mitochondrial homeostasis restoration

During the secondary phase of spinal cord injury (SCI), excessive accumulation of reactive oxygen species (ROS), mitochondrial dysfunction and amplified inflammatory cascades reinforce one another, forming a vicious cycle that drives progressive neuronal damage and limits functional recovery. To enhance lesion-site drug exposure and microenvironment-responsive delivery, we engineered a biomimetic nanoplatform (Ba@Se-MSN&BV2) by loading baicalin into diselenide-bridged mesoporous silica nanoparticles (MSNs) and cloaking them with BV2 microglial membranes, enabling lesion-targeted accumulation and ROS-triggered, on-demand release in ROS-rich lesions. In glutamate-injured HT22 cells and primary hippocampal neurons, Ba@Se-MSN&BV2 reduced ROS, partially restored mitochondrial membrane potential, suppressed apoptosis and enhanced neurite outgrowth, with protection generally exceeding that of free baicalin or Ba@Se-MSN. In lipopolysaccharide-stimulated BV2 microglia, the nanoplatform lowered IL-1β and TNF-α, increased Arg1 and IL-10 and shifted polarization toward an anti-inflammatory, reparative phenotype. In a mouse contusion SCI model, Ba@Se-MSN&BV2 preferentially accumulated at the lesion, mitigated oxidative burden, attenuated glial scarring and preserved axons and neurons. These tissue-level benefits were accompanied by sustained improvements in locomotor recovery and motor-evoked responses. Label-free quantitative proteomics highlighted CHCHD2 as a mitochondria-associated candidate that was downregulated in glutamate-injured neuronal cells and restored by Ba@Se-MSN&BV2. Knockdown/rescue assays supported a contributory role of CHCHD2 in the neuroprotective profile of the nanoplatform. Collectively, Ba@Se-MSN&BV2 mitigates oxidative-inflammatory imbalance during secondary SCI by coupling lesion-targeted homing, ROS-responsive baicalin release and CHCHD2-mediated mitochondrial stabilization, representing a lesion-matched, microenvironment-coupled nanotherapy with translational potential for post-SCI intervention.