Space hampers human exploration due to several environmental stressors, primarily microgravity [1], [2]. Numerous adaptive pathophysiological responses occur, including damages at brain and immune system [3] . Immunosuppression is reported in up to 50% of astronauts, leading to increased susceptibility to infections soon after landing. Specifically, immune cells morphology, differentiation, and function are altered [4]. Microglia, a population of immune cells resident in the brain, is involved in neuroprotection as well as in the shaping of neuronal circuits during brain development [5] . Recent studies performed in microgravity on mice report a critical role of microglia activation in cognitive impairment due to chronic inflammation, at times leading to dysfunctions that interfere with myelin sheath maintenance [6], [7]. The regulation of microglia represents an innovative strategy to mitigate the neurocognitive decline arising in astronauts. The objective of our proposal is the modulation of microglia activation through extracellular vesicles (EVs) during altered gravity exposure, simulated through a random positioning machine. EVs are cell membrane-derived vesicles mediating several activities, including the transport of molecules and intercellular communication [8]. In the brain, the production and exchange of EVs are the primary mechanism of cellular communication and self-regulation. This means EVs mediate the cross-talk among neurons, astrocytes, oligodendrocytes, and microglia, in both physiological and inflammatory processes. The modulation of microglia through EVs has been proven in primary cell cultures, indicating the capability to suppress microglia activity [9]. In addition, EVs capability to cross the blood-brain barrier [10] renders them a promising nanovector to treat brain disease in space, but we expect the output of this proposal to be also relevant to reduce microglia-related brain disorders on Earth.