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Spinal cord injury (SCI) results in severe and often irreversible neurological deficits owing to the disruption of neuronal circuits and the limited regenerative capacity of central nervous system axons. Conventional therapies provide only partial relief, underscoring the need for advanced biomaterial-based interventions. Nanofiber scaffolds that emulate the architecture and biochemical functionality of the native extracellular matrix (ECM) have emerged as powerful platforms to promote axonal regeneration and neural repair. This review synthesizes recent progress in the design of nanofiber scaffolds for SCI, emphasizing strategies that replicate key ECM features—including structural anisotropy, mechanical compliance, and presentation of bioactive ligands. We outline the composition and signaling roles of the healthy brain ECM, describe its pathological remodeling after injury, and relate these changes to the design criteria for functional scaffolds. Current fabrication approaches, particularly electrospinning of natural, synthetic, and hybrid polymers, are discussed in the context of fiber alignment, porosity, and surface functionalization. Mechanistic insights into how these constructs guide axonal extension, modulate glial and immune responses, and support neuronal survival are critically evaluated. Preclinical evidence demonstrates significant anatomical and functional recovery in rodent models, although challenges remain in integration, controlled degradation, immunogenicity, and scalable manufacturing. Finally, emerging directions—including stimulus-responsive and combinatorial scaffold systems—are highlighted as avenues toward clinically translatable solutions for restoring function after SCI.

     

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