An engineered exosome-based platform for targeted delivery to endogenous neural stem cells and fate modulation after spinal cord injury.

Spinal cord injury (SCI) disrupts neural circuits, leading to persistent sensory and motor deficits. However, effective strategies to promote repair through endogenous neural stem cells (eNSCs) are still limited. In this work, we engineered exosomes with a newly identified peptide (TGP1) to achieve targeted delivery to eNSCs. These exosomes were further loaded with Apelin to stimulate eNSC activation and neuronal differentiation. Following tail-vein administration, TGP1-modified exosomes showed greater accumulation in the injured spinal cord and a 4.6-fold increase in co-localization with Nestin+/SOX2+ eNSC-enriched regions compared with unmodified exosomes. Consequently, the Apln-TGP1 group exhibited a 2.9-fold increase in eNSC proliferation (BrdU+/Nestin+), a 3.3-fold increase in newborn neurons (BrdU+/DCX+), and a 4.9-fold increase in BrdU+/NF200+ neuronal-lineage cells compared with the SCI group. Ultimately, the dual-functional treatment was associated with significant improvements in locomotor performance after SCI. Transcriptomic analysis and protein validation indicated that these treatment responses were accompanied by coordinated Apelin-APJ- and PPARγ-related signaling changes. Together, these findings establish a targeted exosomal strategy for modulation of eNSCs and highlight its potential for promoting endogenous repair following SCI.