Bioengineered microglia-targeted exosomes facilitate Aβ clearance via enhancing activity of microglial lysosome for promoting cognitive recovery in Alzheimer's disease

Aggregation of amyloid in the form of senile plaques is currently considered to be one of the main mechanisms driving the development of Alzheimer's disease (AD). Therefore, targeting amyloid homeostasis is an important treatment strategy for AD. Microglia, as the main immune cells, contribute to endocytosis and clearance of amyloid beta (Aβ) via lysosome mediated degradation. As abnormal lysosomal function in microglia is associated with inefficient clearance of Aβ in AD, we designed bioengineered microglia-targeting exosomes to promote the targeted delivery of gemfibrozil (Gem) and restore the lysosomal activity of microglia in clearing Aβ aggregation. Our results suggested that mannose-modified exosomes laden with Gem (MExo-Gem) can not only bind with Aβ but also specifically target microglia through the interaction between Exo-delivered mannose and mannose receptors expressed in microglia, thus promoting Aβ entry into microglia. Exosomal Gem activated lysosomal activity and accelerated lysosome-mediated clearance of Aβ in microglia. Finally, MExo-Gem improved the learning and memory ability of AD model mice.