Alzheimer's disease (AD) is the progressive development of fatal neurodegenerative diseases. Owing to the unclearness of the pathogenesis of AD and the failure of the drug to cross the blood–brain barrier (BBB), there is currently a lack of effective diagnostic and therapeutic approaches in the treatment of AD. The aim of this study was to design exosomes (Exo) as a specifically designed carrier able to carry curcumin (cur) to prevent neuronal death in vitro and in vivo to alleviate the AD symptoms. Our results demonstrated that Exo improved the solubility and bioavailability of cur and increased drug penetration across the BBB by specific active targeting between Exo, inheriting the lymphocyte function-associated antigen 1 (LFA-1) and endothelial intercellular adhesion molecule 1 (ICAM-1). Exosomes derived from curcumin-treated (primed) cells (Exo-cur) can better prevent the death of neurons in vitro and in vivo to relieve the symptoms of AD by inhibiting phosphorylation of the Tau protein through activating the AKT/GSK-3β pathway. Our results suggested that Exo-cur featured highly effective BBB-crossing via receptor-mediated transcytosis to access brain tissues and inhibited Tau phosphorylation, holding great potential in improving targeted drug delivery and the recovery of neuronal function in AD therapy.

Inflammation occurs throughout the progression of cerebral ischemia/reperfusion and mediates myriads of pathological events following an ischemic insult. After ischemic stroke, inflammation was significantly triggered and microglia were activated to phenotypes (M1) typically releasing pro-inflammatory mediators, thus inducing neuron apoptosis and exacerbating brain injury. Therefore, shifting the polarization of microglia from the detrimental pro-inflammatory M1 phenotype to the beneficial anti-inflammatory M2 phenotype seems a promising therapeutic strategy in ischemic stroke. In this study we aimed to investigate the effects of exosomes (Ex) secreted from the lipopolysaccharide (LPS)-stimulated macrophage RAW264.7 cell line (LPS-Ex) on inducing neuroprotection and functional improvement after ischemic stroke by enhancing microglial M2 polarization. The results showed that LPS-Ex treatment exhibited more potent anti-inflammatory and neuroprotective effects in vitro; furthermore it significantly reduced the brain infarct volume and improved neurological function in a rat model of transient focal cerebral ischemia. The beneficial effects of LPS-Ex in ischemic stroke were associated with enhancing microglial polarization from the M1 phenotype to the M2 phenotype and inhibiting inflammation response. In conclusion, LPS-Ex protected against cerebral ischemia by skewing the microglial functional polarity from M1 toward an anti-inflammatory M2 phenotype. It may serve as a novel therapeutic strategy for neuroprotection and functional recovery upon ischemic stroke onset.

Background: The exchange of mitochondria reportedly plays an important role in cell–cell communication in the central nervous system (CNS). The transfer of fragmented and dysfunctional astrocytic mitochondria into neurons and subsequent mitochondrial fusion often cause serious neuronal damage and cerebral ischaemic injury. Methods: In this study, we prepared macrophage-derived exosomes laden with heptapeptide (Hep) as a dynamin-related protein-1 (Drp1)–fission 1 (Fis1) peptide inhibitor P110 to alleviate cerebral ischemia–reperfusion injury by reducing mitochondrial Drp1/Fis1 interaction-mediated astrocytic mitochondrial disorder and promoting the transfer of astrocyte-derived healthy mitochondria into neurons. Results: The results demonstrated that Hep-loaded macrophage-derived exosomes (EXO-Hep) reduced mitochondrial damage in astrocytes by inhibiting the Drp1/Fis1 interaction after ischemia–reperfusion, ensuring the release of heathy astrocytic mitochondria and their subsequent transmission to neurons, alleviating mitochondria-mediated neuronal damage. Conclusion: EXO-Hep significantly mitigated ischemic injury in a model of transient middle cerebral artery occlusion (tMCAO) by reducing the infarct area and improving neurological performance during the process of cerebral ischemia–reperfusion. Graphical

JOURNAL/nrgr/04.03/01300535-202310000-00030/figure1/v/2026-05-25T160659Z/r/image-tiff Exosomes derived from human bone marrow mesenchymal stem cells (MSC-Exo) are characterized by easy expansion and storage, low risk of tumor formation, low immunogenicity, and anti-inflammatory effects. The therapeutic effects of MSC-Exo on ischemic stroke have been widely explored. However, the underlying mechanism remains unclear. In this study, we established a mouse model of ischemic brain injury induced by occlusion of the middle cerebral artery using the thread bolt method and injected MSC-Exo into the tail vein. We found that administration of MSC-Exo reduced the volume of cerebral infarction in the ischemic brain injury mouse model, increased the levels of interleukin-33 (IL-33) and suppression of tumorigenicity 2 receptor (ST2) in the penumbra of cerebral infarction, and improved neurological function. In vitro results showed that astrocyte-conditioned medium of cells deprived of both oxygen and glucose, to simulate ischemia conditions, combined with MSC-Exo increased the survival rate of primary cortical neurons. However, after transfection by IL-33 siRNA or ST2 siRNA, the survival rate of primary cortical neurons was markedly decreased. These results indicated that MSC-Exo inhibited neuronal death induced by oxygen and glucose deprivation through the IL-33/ST2 signaling pathway in astrocytes. These findings suggest that MSC-Exo may reduce ischemia-induced brain injury through regulating the IL-33/ST2 signaling pathway. Therefore, MSC-Exo may be a potential therapeutic method for ischemic stroke.