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      Engineered Exosome for Drug Delivery: Recent Development and Clinical Applications

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          Abstract

          Exosomes are nano-sized membrane vesicles that transfer bioactive molecules between cells and modulate various biological processes under physiological and pathological conditions. By applying bioengineering technologies, exosomes can be modified to express specific markers or carry therapeutic cargo and emerge as novel platforms for the treatment of cancer, neurological, cardiovascular, immune, and infectious diseases. However, there are many challenges and uncertainties in the clinical translation of exosomes. This review aims to provide an overview of the recent advances and challenges in the translation of engineered exosomes, with a special focus on the methods and strategies for loading drugs into exosomes, the pros and cons of different loading methods, and the optimization of exosome production based on the drugs to be encapsulated. Moreover, we also summarize the current clinical applications and prospects of engineered exosomes, as well as the potential risks and limitations that need to be addressed in exosome engineering, including the standardization of exosome preparation and engineering protocols, the quality and quantity of exosomes, the control of drug release, and the immunogenicity and cytotoxicity of exosomes. Overall, engineered exosomes represent an exciting frontier in nanomedicine, but they still face challenges in large-scale production, the maintenance of storage stability, and clinical translation. With continuous advances in this field, exosome-based drug formulation could offer great promise for the targeted treatment of human diseases.

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          Most cited references106

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          The biology, function, and biomedical applications of exosomes

          The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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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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              Progress in Exosome Isolation Techniques

              Exosomes are one type of membrane vesicles secreted into extracellular space by most types of cells. In addition to performing many biological functions particularly in cell-cell communication, cumulative evidence has suggested that several biological entities in exosomes like proteins and microRNAs are closely associated with the pathogenesis of most human malignancies and they may serve as invaluable biomarkers for disease diagnosis, prognosis, and therapy. This provides a commanding impetus and growing demands for simple, efficient, and affordable techniques to isolate exosomes. Capitalizing on the physicochemical and biochemical properties of exosomes, a number of techniques have been developed for the isolation of exosomes. This article summarizes the advances in exosome isolation techniques with an emphasis on their isolation mechanism, performance, challenges, and prospects. We hope that this article will provide an overview of exosome isolation techniques, opening up new perspectives towards the development more innovative strategies and devices for more time saving, cost effective, and efficient isolations of exosomes from a wide range of biological matrices.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                ijn
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                23 December 2023
                2023
                : 18
                : 7923-7940
                Affiliations
                [1 ]Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University , Jinan, People’s Republic of China
                [2 ]School of Public Health, Weifang Medical University , Weifang, People’s Republic of China
                [3 ]School of Public Health, North China University of Science and Technology , Tangshan, People’s Republic of China
                [4 ]School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, People’s Republic of China
                [5 ]Key Laboratory of Birth Defect Prevention and Genetic Medicine of Shandong Health Commission , Jinan, People’s Republic of China
                Author notes
                Correspondence: Lin Zhang, Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University , Jinan, 250001, People’s Republic of China, Tel +86-531-68795046, Email zhanglin8901@163.com
                Shuyin Duan, School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, 250001, People’s Republic of China, Tel +86-13419581411, Email shuyinduan@126.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-5269-9728
                Article
                444582
                10.2147/IJN.S444582
                10752020
                38152837
                89ca1849-5158-45f6-bc12-67f6a04fb5c2
                © 2023 Tian et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 13 October 2023
                : 16 December 2023
                Page count
                Figures: 4, Tables: 2, References: 106, Pages: 18
                Categories
                Review

                Molecular medicine
                engineered exosomes,drug delivery,clinical application,preparation strategy
                Molecular medicine
                engineered exosomes, drug delivery, clinical application, preparation strategy

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