Due to the complex spatial‐temporal pathophysiology of spinal cord injury (SCI), effective modulation of SCI‐specific inflammatory pathogenesis to achieve desirable therapeutic effects on functional recovery still remains challenging. Herein, cell‐enhanced photocrosslinked silk fibroin hydrogels with extracellular matrix‐mimicking cues of mechanical properties and RGD (Arg‐Gly‐Asp) signals are gelled in situ to fill the lesion site to modulate injury‐induced neuroinflammation and promote neurite regrowth after SCI. The bionic hydrogel system provides biomimetic mechanical cues to promote neuronal differentiation of neural stem/progenitor cells (NPCs) and neurite growth by activating YAP nuclear expression. Importantly, favored by the strong capacity of silk fibroin hydrogels on macrophage/microglia recruitment, NPCs encapsulated hydrogel (NPCs@SFRGD0.1) effectively promotes recruited macrophages/microglia to M2 polarization in the lesion site by releasing S100A4 and thereby remodels the inflammatory microenvironment after SCI. Moreover, NPCs@SFRGD0.1 successfully reduces glial scar formation and accelerates corticospinal tract axon regrowth to improve locomotor recovery. Overall, this work contributes to illustrating the therapeutic mechanism of NPCs development based biomaterial therapies on modulating inflammatory microenvironment and this NPCs enhanced silk fibroin hydrogel provides a promising therapeutic strategy for SCI.

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