An engineering-reinforced extracellular vesicle-integrated hydrogel with an ROS-responsive release pattern mitigates spinal cord injury.

The local delivery of mesenchymal stem cell-derived extracellular vesicles (EVs) via hydrogel has emerged as an effective approach for spinal cord injury (SCI) treatment. However, achieving on-demand release of EVs from hydrogel to address dynamically changing pathology remains challenging. Here, we used a series of engineering methods to further enhance EVs' efficacy and optimize their release pattern from hydrogel. Specifically, the pro-angiogenic, neurotrophic, and anti-inflammatory effects of EVs were reinforced through three-dimensional culture and dexamethasone (Dxm) encapsulation. Then, the prepared Dxm-loaded 3EVs (3EVs-Dxm) were membrane modified with ortho-dihydroxy groups (-2OH) and formed an EV-integrated hydrogel (3EVs-Dxm-Gel) via the cross-link with phenylboronic acid-modified hyaluronic acid and tannic acid. The phenylboronic acid ester in 3EVs-Dxm-Gel enabled effective immobilization and reactive oxygen species-responsive release of EVs. Topical injection of 3EVs-Dxm-Gel in SCI rats notably mitigated injury severity and promoted functional recovery, which may offer opportunities for EV-based therapeutics in central nervous system injury.