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Biomaterials can effectively suppress astrocyte activation, but the mechanism remains unclear. Herein, Differentially Expressed Genes (DEGs) are identified through whole transcriptome sequencing in a mouse model of spinal cord injury, revealing the VIM gene as a pivotal regulator in the reactive astrocytes. Moreover, DEGs are predominantly concentrated in the extracellular matrix (ECM). Based on these, 3D injectable electrospun short fibers are constructed to inhibit reactive astrogliosis. Histological staining and functional analysis indicated that fibers with unique 3D network spatial structures can effectively constrain the reactive astrocytes. RNA sequencing and single\u2010cell sequencing results reveal that short fibers downregulate the expression of the <jats:italic>VIM<\/jats:italic> gene in astrocytes by modulating the \u201cECM receptor interaction\u201d pathway, inhibiting the transcription of downstream Vimentin protein, and thereby effectively suppressing reactive astrogliosis. Additionally, fibers block the binding of Vimentin protein with inflammation\u2010related proteins, downregulate the NF\u2010\u03baB signaling pathway, inhibit neuron apoptosis, and consequently promote the recovery of spinal cord neural function. 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