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      Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia

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          Abstract

          Ischemic stroke remains a major cause of death, and anti-inflammatory strategies hold great promise for preventing major brain injury during reperfusion. In the past decade, stem cell-derived extracellular vesicles (EVs) have emerged as novel therapeutic effectors in immune modulation. However, the intravenous delivery of EVs into the ischemic brain remains a challenge due to poor targeting of unmodified EVs, and the costs of large-scale production of stem cell-derived EVs hinder their clinical application.

          Methods: EVs were isolated from a human neural progenitor cell line, and their anti-inflammatory effects were verified in vitro. To attach targeting ligands onto EVs, we generated a recombinant fusion protein containing the arginine-glycine-aspartic acid (RGD)-4C peptide (ACDCRGDCFC) fused to the phosphatidylserine (PS)-binding domains of lactadherin (C1C2), which readily self-associates onto the EV membrane. Subsequently, in a middle cerebral artery occlusion (MCAO) mouse model, the RGD-C1C2-bound EVs (RGD-EV) were intravenously injected through the tail vein, followed by fluorescence imaging and assessment of proinflammatory cytokines expression and microglia activation.

          Results: The neural progenitor cell-derived EVs showed intrinsic anti-inflammatory activity. The RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response. Furthermore, RNA sequencing revealed a set of 7 miRNAs packaged in the EVs inhibited MAPK, an inflammation related pathway.

          Conclusion: These results point to a rapid and easy strategy to produce targeting EVs and suggest a potential therapeutic agent for ischemic stroke.

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          Most cited references50

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          Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.

          To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
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            The biology and function of exosomes in cancer.

            Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40-150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients.
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              The immunology of stroke: from mechanisms to translation

              Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. While the immune system participates in the brain damage produced by ischemia, the damaged brain, in turn, exerts a powerful immunosuppressive effect that promotes fatal intercurrent infections and threatens the survival of stroke patients. Inflammatory signaling is instrumental in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion, to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke, like multiple sclerosis, engages both innate and adaptive immunity. But, unlike multiple sclerosis, adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. However, immunomodulation is not devoid of deleterious side effects, and gaining a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2021
                19 April 2021
                : 11
                : 13
                : 6507-6521
                Affiliations
                [1 ]Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing, Jiangsu Province 211166, China.
                [2 ]Department of Dermatology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu Province 214002, China.
                [3 ]Department of Rehabilitation Medicine, Jiangsu Shengze Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu Province 215228, China.
                [4 ]The Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
                [5 ]Experimental Therapeutics and Molecular Imaging Lab, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, United States.
                Author notes
                ✉ Corresponding author: Jun Gao, Ph.D., E-mail: gaojun@ 123456njmu.edu.cn ; Tian Tian, Ph.D., E-mail: ttian@ 123456njmu.edu.cn .

                #These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov11p6507
                10.7150/thno.56367
                8120222
                33995671
                1017e909-9674-4c45-a5e8-b9c6981ea120
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 24 November 2020
                : 2 April 2021
                Categories
                Research Paper

                Molecular medicine
                extracellular vesicles,exosomes,anti-inflammation,targeted delivery,cerebral ischemia

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