Electroacupuncture synergizes with anti-ferroptosis bioelectrical niche remodeling to promote spinal cord regeneration

Severe spinal cord injury (SCI) frequently causes persistent neurological deficits, and its repair is constrained by multiple pathological factors including deterioration of the microenvironment following secondary injury, massive neuronal loss, interruption of electrical signal conduction, and insufficient endogenous regenerative capacity. Although electroacupuncture (EA) participates in the rehabilitation of SCI by regulating inflammatory responses and promoting the secretion of neurotrophic factors, standalone EA therapy can hardly fully reverse oxidative stress, ferroptosis and neural circuit destruction following severe SCI. Accordingly, this study constructs a conductive anti-ferroptosis hydrogel system (HBP@BMSCs), which utilizes dopamine-grafted hyaluronic acid (HADA) as the bionic matrix, baicalin-polypyrrole (BA-PPy) as the functional component, and is loaded with bone marrow mesenchymal stem cells (BMSCs). This hydrogel system is combined with EA for the repair of severe SCI. The results demonstrate that the HBP hydrogel exhibits favorable cytocompatibility, which can support the survival of BMSCs and maintain their typical mesenchymal stem cell phenotype. In vitro experiments demonstrate that HBP hydrogel effectively alleviates TBHP-induced oxidative stress injury and Erastin-induced ferroptosis-related injury, and exerts a protective effect on BMSCs and PC12 cells. In vivo experiments further confirmed that the combination therapy of HBP@BMSCs with EA significantly downregulated the expression levels of 4HNE, COX2, NOX2, FTH, FTL and TFR after SCI, and restored the expression levels of XCT, GPX4, SOD1 and FPN, thereby alleviating ROS accumulation, lipid peroxidation, iron overload and ferroptosis. With the alleviation of oxidative stress and ferroptosis-related secondary damage, the combination therapy further downregulates the expression of Bax and C-caspase3, upregulates Bcl-2 levels, and significantly inhibits neuronal apoptosis. In addition, the BA-PPy conductive network can synergize with EA to enhance electrical stimulation conduction, upregulate NGF/NGFR and BDNF neurotrophic signaling pathways, and promote the neural lineage differentiation of BMSCs, axon regeneration, corticospinal tract (CST) remodeling, and the recovery of motor function. In conclusion, HBP@BMSCs combined with EA exerts multiple synergistic effects including microenvironment remodeling, anti-ferroptosis protection, stem cell delivery and electroactive neural regeneration, providing a comprehensive therapeutic strategy with translational potential for severe SCI repair.