Dual-engineered imDC-exosome-IKVAV nanovesicles spatiotemporally remodel the neuro-immune microenvironment for spinal cord repair.

Spinal cord injury (SCI) leads to long-term neurological deficits, largely because secondary inflammation and poor intrinsic regeneration prevent effective tissue repair. Existing treatments, including drugs, cell transplantation, and conventional biomaterials, remain limited by insufficient efficacy, safety concerns, and weak coordination between immune regulation and neural reconstruction. Here, we developed an engineered extracellular vesicle platform by decorating immature dendritic cell-derived exosomes with the laminin-mimetic IKVAV peptide via bioorthogonal click chemistry. The resulting imDC-Exo-IKVAV preserved typical exosomal characteristics while integrating the tolerogenic features of imDC-Exo with IKVAV-mediated regenerative cues. In vitro, imDC-Exo-IKVAV reduced macrophage inflammatory activation, promoted an anti-inflammatory phenotype, and enhanced neural stem cell neuronal differentiation. After administration in SCI mice, imDC-Exo-IKVAV accumulated at the injured spinal cord and improved locomotor recovery. Mechanistically, this platform alleviated macrophage infiltration and inflammatory cytokine production, promoted M2-like polarization, enhanced axonal regeneration and remyelination, and restored electrophysiological conduction. These findings suggest that imDC-Exo-IKVAV offers a cell-free therapeutic strategy for SCI by coordinating immune microenvironment remodeling with neural repair.