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

Abstract 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, a platform for AD therapy is developed 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. The EV‐engineering technology provides a potential platform for effective AD therapy by inducing mitophagy.