In the attempt to find a possible cure for Alzheimer’s disease (AD), mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) are being investigated for therapeutic purposes thanks to their protective and anti‐inflammatory properties. The results from this study show that MSC‐EVs operate in dampening inflammation (that favors and accelerates the pathogenic process in AD) and in inducing neuroprotective effects. Furthermore, they sustain the delivery of MSC‐EVs through the intranasal route, being safe and low invasive, thus laying the foundation for a translational future exploitation of MSC‐EVs toward therapy.

Alzheimer’s disease (AD), the most common form of age‐related dementia, is characterized by a slow progressive and detrimental degeneration of the central nervous system (CNS). Neuropathological hallmarks of AD are extracellular β‐amyloid plaques, neurofibrillary tangles, inflammation, synaptic and neuronal dysfunction, and degeneration.1 Inflammation, a concurrent etiopathological mechanisms in AD, is primarily orchestrated by microglia, which represent the innate immune cells of the CNS. They exert also regulatory roles on synaptic plasticity, interacting with neurons by cell‐to‐cell contact or by secreting mediators,23 thus contributing to the remodeling of neural circuits and being involved in learning and memory processes.4

In order to rapidly respond to minimal changes of brain microenvironment, microglia are plastically capable of adopting different and complex activation states, which allow them to contribute either to the cytotoxic response, or to injury resolution and tissue repair.56