JOURNAL/nrgr/04.03/01300535-202302000-00042/figure1/v/2026-05-26T054653Z/r/image-tiff Our previous study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes (hNSC-Exo) in ischemic stroke. Here, we loaded brain-derived neurotrophic factor (BDNF) into exosomes derived from NSCs to construct engineered exosomes (BDNF-hNSC-Exo) and compared their effects with those of hNSC-Exo on ischemic stroke both in vitro and in vivo . In a model of H ₂ O ₂ -induced oxidative stress in NSCs, BDNF-hNSC-Exo markedly enhanced cell survival. In a rat middle cerebral artery occlusion model, BDNF-hNSC-Exo not only inhibited the activation of microglia, but also promoted the differentiation of endogenous NSCs into neurons. These results suggest that BDNF can improve the function of NSC-derived exosomes in the treatment of ischemic stroke. Our research may support the clinical use of other neurotrophic factors for central nervous system diseases.

The aim of the present study was to investigate the neuroprotective roles and mechanisms of the circular RNA circSHOC2 in ischemic-preconditioned astrocyte-derived exosomes (IPAS-EXOs) against ischemic stroke. We established an ischemia model based on oxygen glucose deprivation (OGD) in vitro and isolated resultant exosomes from astrocytes. Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Autophagy-related proteins were analyzed by western blotting. We found that exosomes derived from IPAS-preconditioned medium (IPAS-CM) exerted neuroprotection. Furthermore, circSHOC2 expression was significantly upregulated in exosomes released from IPAS-CM. Overexpression of circSHOC2 in neurons yielded the same protective effects as those from IPAS-EXOs in vitro, and similar results were also observed in the middle cerebral artery occlusion (MCAO) mouse model. Mechanistically, circSHOC2 reduced neuronal apoptosis via regulating autophagy. Furthermore, circSHOC2 was found to sponge miR-7670-3p, which regulated SIRT1 expression. Transfection with an miR-7670-3p small interfering RNA (siRNA) (siRNA-7670-3p) and incubation with circSHOC2 extracellular vesicles attenuated ischemia-induced neuronal apoptosis in vivo and in vitro, while silencing of SIRT1 reversed the protective effects of exosomal circSHOC2 on hypoxic cerebral neurons. Taken together, our findings indicate that circSHOC2 in IPAS-EXOs suppressed neuronal apoptosis and ameliorated neuronal damage by regulating autophagy and acting on the miR-7670-3p/SIRT1 axis, which might contribute to a therapeutic strategy for ischemic stroke treatment.

Transplanted neural stem cells promote neural tissue regeneration and functional recovery primarily by releasing paracrine factors. Exosomes act as important secreted paracrine molecules to deliver therapeutic agents involved in cellular functions. Here, we focused on the role of exosomes (hNSC-Exo) derived from human neural stem cells (hNSCs). We utilized the pro-inflammatory factor interferon gamma (IFN-γ) to induce the generation of altered exosomes (IFN-γ-hNSC-Exo), and compared their roles with those of hNSC-Exo and explored the potential mechanism. Importantly, IFN-γ preconditioning did not affect the secretion, but significantly altered the ability of exosomes derived from hNSCs. Moreover, IFN-γ-hNSC-Exo was functionally superior to hNSC-Exo; showed increased cell proliferation and cell survival and decreased cell apoptosis in vitro. Furthermore, IFN-γ-hNSC-Exo further exerted therapeutic effects (showed better behavioral and structural outcomes) compared to those of hNSCs-Exo in an ischemic stroke rat model. Next-generation sequencing (NGS) revealed specific exosomal miRNAs (hsa-miR-206, hsa-miR-133a-3p and hsa-miR-3656) in IFN-γ-hNSC-Exo with important roles in cell survival. Thus, our findings demonstrate that the inflammatory factor IFN-γ can regulate the functions of exosomes and highlight its role in regulating the application of neural stem cell-derived exosomes.