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

Adv Mater. 2022 Dec;34(49):e2207107. doi: 10.1002/adma.202207107. Epub 2022 Nov 1.


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.

Keywords: Alzheimer's disease; SHP2; engineered extracellular vesicles; mitophagy.

MeSH terms

  • Alzheimer Disease* / therapy
  • Animals
  • Extracellular Vesicles*
  • Mice