Nanoscale Glutathione-Functionalized Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Loaded with Metformin for the Treatment of Spinal Cord Injury

Spinal cord injury (SCI) is a central nervous system disease with a high disability. Immune activation of microglia cells can be induced, and the activated microglia cells are mainly divided into two different subtypes, namely, proinflammatory phenotype (M1) and anti-inflammatory phenotype (M2). Regulating the transformation of microglial subtypes is the key to alleviating inflammation. However, because of the blood–spinal cord barrier (BSCB), most drugs cannot reach the target site and give a full effect. Therefore, the purpose of this study was to design a nanoscale glutathione-functionalized bone marrow mesenchymal stem cell-derived exosome (Exos-GSH) as a delivery carrier for metformin. Using Exos-GSH’s ability to cross BSCB, metformin can be efficiently delivered to the injured spinal cord tissue and taken up by neurons and microglia cells at the injured site. Exos-GSH loading metformin (Exos-Met-GSH) had a particle size of about 154 ± 17 nm, and the encapsulation rate was 87.49 ± 3.36%. In vitro and in vivo experiments showed that Exos-Met-GSH could exert good anti-inflammatory effects by inducing the polarization of microglia from the M1 phenotype to the M2 phenotype. In addition, Exos-Met-GSH can also protect mitochondria by relieving the oxidative stress of neurons, thus inhibiting neuronal apoptosis. Finally, Exos-Met-GSH can protect nerve cells through anti-inflammatory, antioxidant stress, and inhibition of apoptosis, thus promoting the recovery of motor function in SCI mice, which is a potential drug for SCI treatment.