Stroke is the leading neurological cause of death and disability all over the world, with few effective drugs. Nerve growth factor (NGF) is well known for its multifaceted neuroprotective functions post-ischemia. However, the lack of an efficient approach to systemically deliver bioactive NGF into ischemic region hinders its clinical application. In this study, we engineered the exosomes with RVG peptide on the surface for neuron targeting and loaded NGF into exosomes simultaneously, with the resultant exosomes denoted as NGF@Exo. By systemic administration of NGF@Exo, NGF was efficiently delivered into ischemic cortex, with a burst release of encapsulated NGF protein and de novo NGF protein translated from the delivered mRNA. Moreover, NGF@Exo was found to be highly stable for preservation and function efficiently for a long time in vivo. Functional study revealed that the delivered NGF reduced inflammation by reshaping microglia polarization, promoted cell survival, and increased the population of doublecortin-positive cells, a marker of neuroblast. The results of our study suggest the potential therapeutic effects of NGF@Exo for stroke. Moreover, the strategy proposed in our study may shed light on the clinical application of other neurotrophic factors for central nervous system diseases.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.