Delivery of High Mobility Group Box-1 siRNA Using Brain-Targeting Exosomes for Ischemic Stroke Therapy

Kim, Minkyung; Kim, Gyeungyun; Hwang, Do Won; Lee, Minhyung

doi:10.1166/jbn.2019.2866

Cited by 61 publications

(39 citation statements)

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“…In another study, HMGB1-siRNA was loaded into rabies virus glycoprotein (RVG) peptide-decorated exosomes (RVG-Exo) by electroporation and then delivered into the ischemic brain by intravenous injection in an MCAO model. The authors found a more efficient decrease in HMGB1 levels, TNF-α levels, apoptosis in the brain, and infarct volume in the RVG-Exo/HMGB1-siRNA group compared to that in the unmodified exosomes/HMGB1-siRNA group, indicating that RVG-Exo with HMGB1-siRNA may represent a novel therapeutic system for ischemic stroke treatment (Kim et al, 2019a). These findings further provide evidence of a new mechanism of dynamic crosstalk between HMGB1 and cerebral ischemia.…”

Section: Rna Interferencementioning

confidence: 81%

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

Gou

Ying

Yan

et al. 2020

Front. Cell. Neurosci.

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High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.

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Section: Rna Interferencementioning

confidence: 81%

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

Gou

Ying

Yan

et al. 2020

Front. Cell. Neurosci.

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“…To test if serum-derived exosomes are up taken by neural cells, we incubated neuronally differentiated N2a cells, a mouse neuroblastoma cell line, with exosomes labeled with the fluorescent membrane-binding dye PKH67. N2a cells were used as an in vitro model since neuroblastoma cells are an established model for neuronal uptake and biological activity of exosomes [33,36]. Key results were then confirmed using primary cultured neurons.…”

Section: Astrosomes Are Taken Up By Neural Cells and Transport Aβ Andmentioning

confidence: 97%

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Elsherbini

Kirov

Dinkins

et al. 2020

acta neuropathol commun

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Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer's disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβassociated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltagedependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy.

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“…The transfection of donor cells can create EVs with specific peptides within their membrane. Rabies virus glycoprotein (RVG)-derived peptide, which binds p75 neurotrophin receptor, was conjugated to EVs, and then siRNA was loaded through electroporation [1,121,122]. Chen et al conjugated klotho protein to EVs, which binds circulating endothelial progenitor cells (EPCs).…”

Section: Sirnamentioning

confidence: 99%

Overview and Update on Methods for Cargo Loading into Extracellular Vesicles

et al. 2021

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The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells. Growing evidence shows that EVs have great potential to serve as effective drug carriers. Since EVs can not only transfer biological information, but also effectively deliver hydrophobic drugs into cells, the application of EVs as a novel drug delivery system has attracted considerable scientific interest. Recently, EVs loaded with siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, or therapeutic drugs show improved delivery efficiency and drug effect. In this review, we summarize the methods used for the cargo loading into EVs, including siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, and therapeutic drugs. Furthermore, we also include the recent advance in engineered EVs for drug delivery. Finally, both advantages and challenges of EVs as a new drug delivery system are discussed. Here, we encourage researchers to further develop convenient and reliable loading methods for the potential clinical applications of EVs as drug carriers in the future.

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Delivery of High Mobility Group Box-1 siRNA Using Brain-Targeting Exosomes for Ischemic Stroke Therapy

Cited by 61 publications

References 0 publications

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Overview and Update on Methods for Cargo Loading into Extracellular Vesicles

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