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Exosomes make a significant contribution during stem cell-based therapy due to the abundant contents. Accumulating evidence implies exosomes can act as potential biological nano agents. We herein propose hypoxic preconditioning for neural stem cells (NSCs) that could produce hypoxic exosomes for efficient treatment of ischemic stroke. Hypoxic preconditioning on NSCs significantly altered the miRNAs encapsulated in exosomes. Notably, hypoxic exosomes could target the injured brain to regulate the microenvironment to inhibit neuroinflammation and promote blood–brain barrier permeability recovery. Additionally, the autologous NSCs in Nestin-CreER mice could be activated by hypoxic exosomes to facilitate nerve regeneration. After hypoxic preconditioning, exosomes further exerted therapeutic effects on both survival (25%) and behavioral outcomes in ischemic stroke mice. Overall, hypoxic preconditioning NSCs can produce effective nano agent and may represent a promising strategy for clinical neurorestorative therapy.
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