Neurodegenerative diseases are characterized by a progressive and irreversible loss of neuronal cells leading to cognitive impairments and memory loss. Despite being a powerful tool for clinical applications, the use of mesenchymal stromal cells (MSCs) imposes several challenges in terms of delivery, safety and variability. MSCs exert their regenerative effects through a paracrine mode of action, also known as the secretome that is composed of cytokines, chemokines, growth factors, proteins and extracellular vesicles – namely the microvesicles and the exosomes. It has been reported that preconditioning of MSCs alters the molecular composition of their secretome, thereby improving their therapeutic potential. Based on our previous work and other reports, we propose a unique strategy, comprising of the following parameters, for harnessing the true potential of the extracellular vesicles isolated from the primed MSCs for promoting neuroregeneration: i) examining the signaling mechanisms prevailing in the MSCs, ii) assessing the age of the MSC donor, iii) priming MSCs with neurotrophic factors and examining the expression of neuronal and autophagy markers in them, and iv) examining the extracellular vesicles for autophagy-promoting-neurotrophic factors. We speculate that our strategy may provide an impetus for improving the efficacy of MSCs in reversing the process of neurodegeneration.