Engineered Extracellular Vesicles with SHP2 High Expression Promote Mitophagy for Alzheimer's Disease Treatment

Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment of existing Mitophagy inducers limit their further applications. In this study, we develops a platform for AD therapy using nanosized mesenchymal stem cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability of MSC-EVs-SHP2 is demonstrated in AD-mice, facilitating SHP2 delivery to the brain. In addition, MSC-EVs-SHP2 significantly induces Mitophagy of neuronal cells, which alleviates mitochondrial damage-mediated Apoptosis and NLRP3 inflammasome activation. Mitophagy further diminishes neuronal cells Apoptosis and neuroinflammation, culminating with rescued synaptic loss and cognitive decline in an AD mouse model. Our EV-engineering technology provide a potential platform for effective AD therapy by inducing Mitophagy. This article is protected by copyright. All rights reserved.