Journal
ADVANCED MATERIALS
Volume 34, Issue 49, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.202207107
Keywords
Alzheimer's disease; engineered extracellular vesicles; mitophagy; SHP2
Categories
Funding
- National Natural Science Foundation of China [32022043]
- National Research Programs of China [2022YFB3800175]
- Suzhou Key Laboratory of Nanotechnology and Biomedicine, Collaborative Innovation Center of Suzhou Nano Science Technology
- 111 Project
- Joint International Research Laboratory of Carbon-Based Functional Materials and Devices
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This study develops a platform for Alzheimer's disease (AD) therapy using nanosized mesenchymal-stem-cells-derived extracellular vesicles with high expression of tyrosine phosphatase-2 (SHP2). The platform demonstrates high blood-brain barrier penetration ability, delivers SHP2 to the brain, and induces significant mitophagy of neuronal cells, thereby alleviating mitochondrial damage, apoptosis, and neuroinflammation, leading to improved synaptic loss and cognitive decline in an AD mouse model.
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.
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