Sustained Delivery of Exosome-Encapsulated Ellagic Acid via Injectable Self-Healing Hydrogel for Spinal Cord Injury Repair.

Following primary mechanical trauma, spinal cord injury evolves through a complex secondary cascade involving blood-spinal cord barrier disruption, ischemia-reperfusion injury, oxidative stress, and neuroinflammation, which collectively propagate neuronal death, demyelination, and glial scarring to preclude functional recovery. Current treatments mitigate single processes but not all at once, limiting their efficacy. To develop an effective multivalent treatment, the small molecule ellagic acid, which inhibits inflammation and oxidative damage while protecting the barrier between blood and spinal cord, was encapsulated within exosomes derived from bone marrow mesenchymal stem cells. These exosomes, by themselves, have been shown to promote neural repair, and loading ellagic acid into them stabilized the drug and increased its bioavailability. The ellagic acid-loaded exosomes (Exos-EA) were formulated into a self-healing chitosan/hyaluronic acid hydrogel (Exos-EA@CS/HA-Gel) to prolong their retention and release at the injection site. The resulting Exos-EA@CS/HA-Gel inhibited lipopolysaccharide-induced inflammatory responses in murine microglial cultures and protected human neuroblastoma cell lines from death due to oxidative stress. In a rat model of spinal cord injury, Exos-EA@CS/HA-Gel restored the function of the barrier between blood and spinal cord, promoting tissue repair. These results suggest that Exos-EA@CS/HA-Gel may be effective against spinal cord injury.