Abstract
The recovery of neurological function following spinal cord injury (SCI) is primarily constrained by two core pathological mechanisms: neuroinflammation and impaired tissue regeneration. While extracellular vesicles (EVs) have emerged as a promising therapeutic approach, their clinical translation remains limited by the inherent low bioactivity of natural EVs and suboptimal targeting efficiency at lesion sites. In this study, we developed a targeted EV delivery system with synergistic therapeutic potential, termed C-A/R-EVs, through a multidimensional engineering strategy. Specifically, the system leverages the blood-spinal cord barrier-penetrating ability of Angiopep-2 and the pathologically neovascular targeting capability of RGD to achieve precise localization in the SCI region. Additionally, a curcumin pretreatment strategy is employed to enhance the anti-inflammatory and neuroregenerative properties of the EVs. SnRNA-seq reveals that C-A/R-EVs reprogram microglia from a pro-inflammatory phenotype to a reparative phenotype, effectively suppressing neuroinflammation and promoting neural repair. Mechanistically, C-A/R-EVs facilitate axonal regeneration through enhancing the phagocytosis of myelin debris via reparative microglia, while simultaneously reducing the presence of inflammatory microglia to mitigate postinjury neuroinflammation. Moreover, C-A/R-EVs contribute to the restoration of the blood-spinal cord barrier. This study provides new insights into the design and fabrication of engineered EVs to synergistically enhance spinal cord repair through multimodal mechanisms.