Self-Assembling Tetramethylpyrazine-Glycyrrhizic acid hydrogel inhibits microglial pyroptosis in spinal cord injury via the NETs/cGAS/STING pathway

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Spinal cord injury (SCI) is a severe central nervous system disorder characterized by irreversible damage and lifelong disability, with few effective treatment options. Tetramethylpyrazine (TMP), a bioactive compound from Ligusticum wallichii , has shown promise in SCI therapy. However, its clinical use is limited by poor water solubility, a short half-life, and restricted blood-spinal cord barrier penetration. To address these challenges, a novel self-assembling hydrogel (GAT-H) was developed, utilizing the amphiphilic nature of glycyrrhizic acid (GA) to encapsulate TMP through non-covalent interactions. This environmentally friendly, crosslinker-free formulation produces a uniform, injectable hydrogel with a porous microstructure that matches the mechanical stiffness of spinal cord tissue. It exhibits shear-thinning and self-healing properties, enabling minimally invasive, in situ gelation at irregular lesion sites. Mechanistic studies showed that GAT-H ensures sustained TMP release, inhibiting neutrophil extracellular trap (NET) formation and subsequently blocking the NET-activated cGAS/STING pathway in microglia, which attenuates NLRP3 inflammasome-mediated pyroptosis. Functional assessments revealed significant motor recovery improvements, as indicated by gait analysis. These results position GAT-H as a promising therapeutic platform that combines GA-based self-assembly with TMP’s therapeutic efficacy, offering a preclinical basis for the use of natural product-based hydrogels in SCI treatment.