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.