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Review 回顾

Clinical Applications of Exosomes: A Critical Review
外泌体的临床应用:批判性评论

Kar Wai Alvin Lee 1 1 ^(1){ }^{1}, Lisa Kwin Wah Chan 1 1 ^(1){ }^{1}, Lee Cheuk Hung 1 1 ^(1){ }^{1}, Lam Kar Wai Phoebe 2 D 2 D ^(2)^(D){ }^{2}{ }^{\mathbb{D}}, Youngjin Park 3 3 ^(3){ }^{3} and Kyu-Ho Yi 4 , 5 , ( D ) 4 , 5 , ( D ) ^(4,5,**(D)){ }^{4,5, *(\mathbb{D})}
Kar Wai Alvin Lee 1 1 ^(1){ }^{1} 李伟 , Lisa Kwin Wah Chan 1 1 ^(1){ }^{1} , Lee Cheuk Hung 1 1 ^(1){ }^{1} , Lam Kar Wai Phoebe 2 D 2 D ^(2)^(D){ }^{2}{ }^{\mathbb{D}} , Youngjin Park 3 3 ^(3){ }^{3} 和 Kyu-Ho Yi 4 , 5 , ( D ) 4 , 5 , ( D ) ^(4,5,**(D)){ }^{4,5, *(\mathbb{D})}
1 EverKeen Medical Centre, Hong Kong; alvin429@yahoo.com (K.W.A.L.); drchan.everkeen@gmail.com (L.K.W.C.); andylee618@hotmail.com (L.C.H.)
1 香港恒基医疗中心;alvin429@yahoo.com (K.W.A.L.);drchan.everkeen@gmail.com (L.K.W.C.);andylee618@hotmail.com (L.C.H.)
2 Perfect Skin Solution, Hong Kong; drlamkarwai@gmail.com
2 Perfect Skin Solution,香港;drlamkarwai@gmail.com
3 Obliv Clinic, Incheon 21998, Republic of Korea; younginp@gmail.com
3 Obliv Clinic, 仁川 21998, 大韩民国;younginp@gmail.com
4 Division in Anatomy and Developmental Biology, Department of Oral Biology, Human Identification Research Institute, BK21 FOUR Project, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
4 延世大学牙科学院 BK21 FOUR 项目,人类身份鉴定研究所口腔生物学系解剖学与发育生物学教研室,首尔特别市西大门区延世路 50-1 邮轮 03722
5 Maylin Clinic (Apgujeong), Seoul B1F 450, Republic of Korea
5 Maylin Clinic (狎鸥亭), 首尔 B1F 450, 大韩民国
* Correspondence: kyuho90@daum.net; Tel.: +82-2-2228-3047; Fax: +82-2-393-8076
* 通信方式:kyuho90@daum.net;电话:+82-2-2228-3047;传真:+82-2-393-8076

Citation: Lee, K.W.A.; Chan, L.K.W.; Hung, L.C.; Phoebe, L.K.W.; Park, Y.; Yi, K.-H. Clinical Applications of Exosomes: A Critical Review. Int. J. Mol. Sci. 2024, 25, 7794. https:// doi.org/10.3390/ijms25147794
引自:Lee, K.W.A.;陈,L.K.W.;洪,LC;菲比,LKW;帕克,Y.;易 K.-H.外泌体的临床应用:批判性评论。国际分子科学杂志 2024, 25, 7794。https:// doi.org/10.3390/ijms25147794
Academic Editor: Atsushi Matsuzawa
学术编辑:Atsushi Matsuzawa
Received: 3 July 2024 收稿日期: 2024-07-03
Revised: 12 July 2024 修订日期:2024 年 7 月 12 日
Accepted: 15 July 2024 录用日期: 2024-07-15
Published: 16 July 2024 已发布: 16 七月 2024
Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
版权所有:©作者 2024 年。被许可人 MDPI,瑞士巴塞尔。本文是根据知识共享署名 (CC BY) 许可证 (https:// creativecommons.org/licenses/by/ 4.0/) 的条款和条件分发的开放获取文章。

Abstract 抽象

Exosomes, small membrane-bound vesicles secreted by cells, have gained significant attention for their therapeutic potential. Measuring 30 100 nm 30 100 nm 30-100nm30-100 \mathrm{~nm} in diameter and derived from various cell types, exosomes play a crucial role in intercellular communication by transferring proteins, lipids, and RNA between cells. This review analyzes existing literature on the clinical applications of exosomes. We conducted a comprehensive search of peer-reviewed articles and clinical trial data to evaluate the benefits, limitations, and challenges of exosome-based therapies. Key areas of focus included regenerative medicine, cancer therapy, gene therapy, and diagnostic biomarkers. This review highlights the vast clinical applications of exosomes. In regenerative medicine, exosomes facilitate tissue repair and regeneration. In cancer therapy, exosomes can deliver therapeutic agents directly to tumor cells. In gene therapy, exosomes serve as vectors for gene delivery. As diagnostic biomarkers, they are useful in diagnosing various diseases. Challenges such as the isolation, purification, and characterization of exosomes were identified. Current clinical trials demonstrate the potential of exosome-based therapies, though they also reveal significant hurdles. Regulatory issues, including the need for standardization and validation of exosome products, are critical for advancing these therapies. While significant progress has been made in understanding exosome biology, further research is essential to fully unlock their clinical potential. Addressing challenges in isolation, purification, and regulatory standardization is crucial for their successful application in clinical practice. This review provides a concise overview of the clinical applications of exosomes, emphasizing both their therapeutic promise and the obstacles that need to be overcome.
外泌体是细胞分泌的膜结合小囊泡,因其治疗潜力而受到广泛关注。外泌体的直径来自 30 100 nm 30 100 nm 30-100nm30-100 \mathrm{~nm} 各种细胞类型,通过在细胞之间转移蛋白质、脂质和 RNA,在细胞间通讯中起着至关重要的作用。本文分析了有关外泌体临床应用的现有文献。我们对同行评议的文章和临床试验数据进行了全面检索,以评估基于外泌体的疗法的好处、局限性和挑战。重点领域包括再生医学、癌症治疗、基因治疗和诊断生物标志物。这篇综述重点介绍了外泌体的广泛临床应用。在再生医学中,外泌体促进组织修复和再生。在癌症治疗中,外泌体可以将治疗剂直接输送到肿瘤细胞。在基因治疗中,外泌体用作基因递送的载体。作为诊断生物标志物,它们可用于诊断各种疾病。确定了外泌体的分离、纯化和表征等挑战。目前的临床试验证明了基于外泌体的疗法的潜力,尽管它们也揭示了重大障碍。监管问题,包括外泌体产品的标准化和验证需求,对于推进这些疗法至关重要。虽然在了解外泌体生物学方面取得了重大进展,但进一步的研究对于充分释放其临床潜力至关重要。解决分离、纯化和监管标准化方面的挑战对于它们在临床实践中的成功应用至关重要。 这篇综述简要概述了外泌体的临床应用,强调了它们的治疗前景和需要克服的障碍。

Keywords: exosomes; therapeutic potential; regenerative medicine; cancer therapy; diagnostic biomarkers
关键词:外泌体;治疗潜力;再生医学;癌症治疗;诊断生物标志物

1. Comprehensive Background
1. 综合背景

Exosomes, small membrane-bound vesicles secreted by cells, have garnered significant attention in recent years due to their potential therapeutic applications. These tiny particles, measuring between 30 and 100 nanometers in diameter, are derived from various cell types, including stem cells, immune cells, and cancer cells (Figure 1) [1-3]. Initially discovered as a means of cellular waste disposal, exosomes have been found to play a crucial role in intercellular communication, facilitating the transfer of proteins, lipids, and RNA between cells [3,4] (Figure 2).
外泌体是细胞分泌的小膜结合囊泡,由于其潜在的治疗应用,近年来引起了广泛关注。这些直径在 30 到 100 纳米之间的微小颗粒来源于各种细胞类型,包括干细胞、免疫细胞和癌细胞(图 1)[1-3]。外泌体最初被发现是作为细胞废物处理的一种手段,已被发现在细胞间通讯中起着至关重要的作用,促进蛋白质、脂质和 RNA 在细胞之间的转移 [3,4](图 2)。
The clinical applications of exosomes are vast and multifaceted. One of the most promising areas of research is in the field of regenerative medicine, where exosomes derived from stem cells have been shown to promote tissue repair and regeneration. For example, exosomes have been used to treat cardiac diseases, such as myocardial infarction,
外泌体的临床应用广泛且多方面。最有前途的研究领域之一是再生医学领域,其中源自干细胞的外泌体已被证明可以促进组织修复和再生。例如,外泌体已被用于治疗心脏病,如心肌梗塞、

by promoting angiogenesis and improving cardiac function. Similarly, exosomes have been explored as a therapeutic agent for the treatment of neurological disorders, including Parkinson’s disease and Alzheimer’s disease [5,6].
通过促进血管生成和改善心脏功能。同样,外泌体已被探索作为治疗神经系统疾病(包括帕金森病和阿尔茨海默病)的治疗剂[5,6]。

Figure 1. This Figure illustrates the relative sizes of various biological entities. Exosomes, ranging from 30 to 100 nm , are comparable in size to viruses. Larger extracellular vesicles, known as microvesicles, fall within the 100 nm to 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} range. Apoptotic bodies, which are even larger, measure between 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} and 5 μ m 5 μ m 5mum5 \mu \mathrm{~m}. For comparison, platelets are in the 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} to 5 μ m 5 μ m 5mum5 \mu \mathrm{~m} range, while cells are significantly larger, measuring 8 12 μ m 8 12 μ m 8-12 mum8-12 \mu \mathrm{~m}. This Figure highlights the size scale from exosomes to cells, demonstrating the hierarchical structure of these biological components.
图 1.该图说明了各种生物实体的相对大小。外泌体,范围从 30 到 100 nm ,大小与病毒相当。较大的细胞外囊泡,称为微泡,落在 100 nm 范围内 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} 。凋亡小体,甚至更大,测量在 和 5 μ m 5 μ m 5mum5 \mu \mathrm{~m} 之间 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} 。相比之下,血小板在 1 μ m 1 μ m 1mum1 \mu \mathrm{~m} to 5 μ m 5 μ m 5mum5 \mu \mathrm{~m} 范围内,而细胞明显更大,测量 8 12 μ m 8 12 μ m 8-12 mum8-12 \mu \mathrm{~m} .该图突出显示了从外泌体到细胞的大小尺度,展示了这些生物成分的层次结构。

Figure 2. Exosomes between the cells (purple-colored) function as intercellular communicators, facilitating the transfer of proteins (green), lipids (red), and RNA (blue).
图 2.细胞之间的外泌体(紫色)起细胞间通讯器的作用,促进蛋白质(绿色)、脂质(红色)和 RNA(蓝色)的转移。
In addition to their therapeutic potential, exosomes have also been studied for their diagnostic capabilities. Exosomal biomarkers have been identified for various diseases, including cancer, allowing for the development of non-invasive diagnostic tests [7,8]. Furthermore, exosomes have been explored as a means of delivering targeted therapeutics to specific cells or tissues, circumventing the limitations of traditional delivery methods [9].
除了它们的治疗潜力外,外泌体的诊断能力也受到了研究。已经确定了包括癌症在内的各种疾病的外泌体生物标志物,从而可以开发无创诊断测试 [7,8]。此外,外泌体已被探索作为一种向特定细胞或组织递送靶向治疗药物的手段,规避了传统递送方法的局限性 [9]。
Despite the significant progress that has been made in the field of exosome research, there are still many challenges and uncertainties that need to be addressed. For example, the optimal methods for isolating and purifying exosomes are still being debated, and the stability and bioavailability of exosomal cargo remain a concern [10,11]. Furthermore, the regulatory environment surrounding the use of exosomes as a therapeutic agent is still evolving [12].
尽管外泌体研究领域取得了重大进展,但仍有许多挑战和不确定性需要解决。例如,分离和纯化外泌体的最佳方法仍在争论中,外泌体货物的稳定性和生物利用度仍然是一个问题[10,11]。此外,围绕使用外泌体作为治疗剂的监管环境仍在不断发展 [12]。
This critical review aims to provide a comprehensive overview of the current state of knowledge in the field of clinical applications of exosomes. Through a critical analysis of the existing literature, we will explore the benefits and limitations of exosomes as a therapeutic agent, discuss the challenges and uncertainties that need to be addressed, and provide recommendations for future research directions.
本批判性综述旨在全面概述外泌体临床应用领域的知识现状。通过对现有文献的批判性分析,我们将探索外泌体作为治疗剂的好处和局限性,讨论需要解决的挑战和不确定性,并为未来的研究方向提供建议。
Keywords including “Exosome”, “Diagnostic” “Therapy”, “Therapeutic”, “Clinical Application”, and “Clinical Implication” were searched in the MEDLINE, PubMed, and Ovid databases for relevant studies published on clinical trials, diagnosis, and treatment. Some papers were further reviewed using a double-blinding approach, sample size, control usage, randomization usage, and objective endpoint measurements. All studies were classified according to the Oxford Center for evidence-based medicine evidence hierarchy.
在 MEDLINE、PubMed 和 Ovid 数据库中搜索了包括“外泌体”、“诊断”、“治疗”、“临床应用”和“临床意义”在内的关键词,以查找已发表的有关临床试验、诊断和治疗的相关研究。使用双盲方法、样本量、对照使用、随机化使用和客观终点测量进一步审查了一些论文。所有研究均根据牛津循证医学证据层次结构中心进行分类。

2. Chemical Properties of Exosomes
2. 外泌体的化学性质

Hu et al. [13] reviews the clinical applications of exosome membrane proteins. The authors discuss the importance of exosomes in disease diagnosis, prognosis, and treatment. They highlight the potential of exosome membrane proteins as biomarkers for various diseases, including cancer, cardiovascular disease, and neurodegenerative disorders. The authors also review the use of exosomes as therapeutic agents, including their ability to deliver therapeutic cargo and modulate immune responses. The paper concludes that further research is needed to fully understand the potential benefits and risks of exosome membrane proteins (Level 5).
胡 等 [13] 综述了外泌体膜蛋白的临床应用。作者讨论了外泌体在疾病诊断、预后和治疗中的重要性。他们强调了外泌体膜蛋白作为各种疾病(包括癌症、心血管疾病和神经退行性疾病)的生物标志物的潜力。作者还回顾了外泌体作为治疗剂的使用,包括它们传递治疗货物和调节免疫反应的能力。该论文得出结论,需要进一步研究以充分了解外泌体膜蛋白的潜在益处和风险(5 级)。
Santos and Almeida [14] provide an overview of the development of exosome-based vaccines, highlighting their potential as a novel approach to vaccine design. The authors review the history of exosome-based vaccines, from the discovery of exosomes in the 1980s to the current state of research. They discuss the advantages of exosomes as vaccine carriers, including their ability to deliver multiple antigens, modulate immune responses, and potentially induce long-term immunity. The authors also summarize ongoing clinical trials evaluating exosome-based vaccines for various diseases, including cancer, infectious diseases, and autoimmune disorders. The paper concludes that while exosome-based vaccines show promising results, further research is needed to fully elucidate their potential and address challenges associated with their development and manufacturing (Level 3b).
Santos 和 Almeida [14] 概述了基于外泌体的疫苗的开发,强调了它们作为疫苗设计新方法的潜力。作者回顾了基于外泌体的疫苗的历史,从 1980 年代发现外泌体到目前的研究状态。他们讨论了外泌体作为疫苗载体的优势,包括它们传递多种抗原、调节免疫反应和可能诱导长期免疫的能力。作者还总结了正在进行的临床试验,这些试验评估了基于外泌体的疫苗治疗各种疾病,包括癌症、传染病和自身免疫性疾病。该论文得出的结论是,虽然基于外泌体的疫苗显示出有希望的结果,但需要进一步的研究来充分阐明它们的潜力并解决与其开发和制造相关的挑战(3b 级)。
Song et al. [15] provides an overview of the emerging role of exosomes as novel therapeutics. The authors discuss the biology of exosomes, including their composition, formation, and function, as well as their potential applications in various diseases. They also review the current technologies used to isolate, purify, and characterize exosomes, as well as the clinical applications of exosomes in cancer, regenerative medicine, and immunotherapy. The authors highlight the advantages and challenges of exosome-based therapies, including their potential for targeted delivery, low toxicity, and immune tolerance. Finally, they discuss the future directions and next steps for exosome research and development (Level 5).
Song 等 [15] 概述了外泌体作为新型疗法的新兴作用。作者讨论了外泌体的生物学特性,包括它们的组成、形成和功能,以及它们在各种疾病中的潜在应用。他们还回顾了当前用于分离、纯化和表征外泌体的技术,以及外泌体在癌症、再生医学和免疫治疗中的临床应用。作者强调了基于外泌体的疗法的优势和挑战,包括它们在靶向递送、低毒性和免疫耐受方面的潜力。最后,他们讨论了外泌体研究和开发的未来方向和下一步(第 5 级)。
Aheget et al. [16] reviews the potential of exosomes as a new player in translational nanomedicine. The authors discuss the unique characteristics of exosomes, including their natural origin, biocompatibility, and ability to deliver therapeutic agents. They highlight the advantages of exosomes over traditional nanoparticles, including their ability to evade the immune system and target specific cells. The authors review the current applications of exosomes in nanomedicine, including their use as carriers for drugs, genes, and siRNAs. They also discuss the challenges and limitations associated with the use of exosomes, including their isolation and purification methods and their potential for immune rejection (Level 5).
Aheget等[16]回顾了外泌体作为转化纳米医学新参与者的潜力。作者讨论了外泌体的独特特性,包括它们的天然来源、生物相容性和递送治疗剂的能力。他们强调了外泌体相对于传统纳米颗粒的优势,包括它们逃避免疫系统和靶向特定细胞的能力。作者回顾了外泌体在纳米医学中的当前应用,包括它们作为药物、基因和 siRNA 载体的用途。他们还讨论了与使用外泌体相关的挑战和限制,包括它们的分离和纯化方法以及它们可能产生的免疫排斥反应(5 级)。
Wang et al. [17] provides a comprehensive review of the recent progress in exosome research, focusing on their isolation, characterization, and clinical applications. The authors discuss the current methods for isolating and characterizing exosomes, including the use of novel biomarkers and techniques. They also highlight the clinical applications of exosomes, including their potential as diagnostic and therapeutic biomarkers for cancer and other diseases. The authors also explore the challenges and limitations of exosome research, including the need for standardized methods and the potential for contamination (Level 5).
Wang等[17]对外泌体研究的最新进展进行了全面综述,重点介绍了外泌体研究的分离、表征和临床应用。作者讨论了当前分离和表征外泌体的方法,包括新型生物标志物和技术的使用。他们还强调了外泌体的临床应用,包括它们作为癌症和其他疾病的诊断和治疗生物标志物的潜力。作者还探讨了外泌体研究的挑战和局限性,包括对标准化方法的需求和污染的可能性(5 级)。
Hood and Wickline [18] provide a systematic approach to the development of exosomebased translational nanomedicine. The authors highlight the potential of exosomes as a delivery platform for therapeutic agents, including siRNAs, miRNAs, and proteins. They discuss the current challenges and limitations in the development of exosome-based therapies, including the need for standardized methods for isolating and characterizing exosomes, as well as the potential for immune recognition and clearance. The authors propose a systematic approach to exosome-based translational nanomedicine, which involves the development of a comprehensive framework for designing, testing, and implementing exosome-based therapies (Level 5).
Hood 和 Wickline [18] 为基于外泌体的转化纳米医学的开发提供了一种系统的方法。作者强调了外泌体作为治疗剂(包括 siRNA、miRNA 和蛋白质)递送平台的潜力。他们讨论了基于外泌体的疗法开发的当前挑战和局限性,包括分离和表征外泌体的标准化方法的需求,以及免疫识别和清除的潜力。作者提出了一种基于外泌体的转化纳米医学的系统方法,其中涉及开发一个用于设计、测试和实施基于外泌体的疗法的综合框架(第 5 级)。
Donoso-Quezada et al. [19] provides a comprehensive review of the current state-of-the-art exosome loading and functionalization techniques for enhanced therapeutics. The authors discuss the various methods used to load and functionalize exosomes with therapeutic molecules, such as siRNAs, miRNAs, and proteins. They highlight the importance of understanding the molecular mechanisms of exosome-mediated delivery and the potential challenges and limitations of exosome-based therapies. The authors also review the recent advancements in exosome loading and functionalization techniques, including the use of nanoparticles, liposomes, and biodegradable polymers (Level 2c).
Donoso-Quezada等[19]全面综述了当前最先进的外泌体加载和功能化技术,以增强治疗效果。作者讨论了用于用治疗性分子(如 siRNA、miRNA 和蛋白质)加载和功能化外泌体的各种方法。他们强调了了解外泌体介导递送的分子机制的重要性以及基于外泌体的疗法的潜在挑战和局限性。作者还回顾了外泌体加载和功能化技术的最新进展,包括纳米颗粒、脂质体和可生物降解聚合物(2c 级)的使用。
Das et al. [20] explores the potential of exosomes as a novel delivery platform for therapeutics across biological barriers. The authors discuss the unique features of exosomes, including their ability to cross cell membranes, evade immune recognition, and target specific cells. They review the current state of exosome-based delivery systems, including their use in cancer therapy, regenerative medicine, and infectious disease treatment. The authors also highlight the potential challenges and limitations of exosome-based therapies, including the need for standardization and scalability of exosome production (Level 3b).
Das 等 [20] 探讨了外泌体作为跨生物屏障治疗的新型递送平台的潜力。作者讨论了外泌体的独特特征,包括它们穿过细胞膜、逃避免疫识别和靶向特定细胞的能力。他们回顾了基于外泌体的递送系统的现状,包括它们在癌症治疗、再生医学和传染病治疗中的应用。作者还强调了基于外泌体的疗法的潜在挑战和局限性,包括外泌体生产的标准化和可扩展性(3b 级)的需求。
Gurunathan et al. [21] provides a comprehensive review of the factors influencing exosome biogenesis, functions, and therapeutic applications. The authors discuss the role of various biological and environmental factors, including cell type, cell culture conditions, and disease state, in shaping exosome composition and function. They also review the current understanding of exosome-mediated cellular communication, including the transfer of proteins, lipids, and RNA molecules between cells. The authors highlight the potential therapeutic applications of exosomes, including their use in cancer treatment, regenerative medicine, and gene therapy. Additionally, they discuss the challenges and limitations associated with exosome-based therapies, including exosome isolation and purification, and the need for further research to fully understand their mechanisms of action (Level 3b).
Gurunathan等[21]全面综述了影响外泌体生物发生、功能和治疗应用的因素。作者讨论了各种生物和环境因素(包括细胞类型、细胞培养条件和疾病状态)在塑造外泌体组成和功能中的作用。他们还回顾了目前对外泌体介导的细胞通讯的理解,包括蛋白质、脂质和 RNA 分子在细胞之间的转移。作者强调了外泌体的潜在治疗应用,包括它们在癌症治疗、再生医学和基因治疗中的应用。此外,他们还讨论了与基于外泌体的疗法相关的挑战和局限性,包括外泌体分离和纯化,以及进一步研究以充分了解其作用机制的必要性(3b 级)。
Zhang et al. [22] provides a comprehensive review of exosomes, including their classification, isolation techniques, storage, and applications in diagnosis and targeted therapy. The authors discuss the different types of exosomes, including extracellular vesicles, microvesicles, and apoptotic bodies, and highlight the importance of standardization in exosome isolation and characterization. They also review various methods for isolating exosomes, including ultracentrifugation, density gradient centrifugation, and immuneaffinity chromatography. The authors discuss the potential of exosomes as diagnostic biomarkers for various diseases, as well as their use in targeted therapy for cancer and other diseases. They also highlight the challenges associated with exosome-based therapies, including the need for improved understanding of exosome biology and the development of standardized manufacturing processes (Level 5).
Zhang等[22]对外泌体进行了全面的综述,包括它们的分类、分离技术、储存以及在诊断和靶向治疗中的应用。作者讨论了不同类型的外泌体,包括细胞外囊泡、微泡和凋亡小体,并强调了标准化在外泌体分离和表征中的重要性。他们还回顾了分离外泌体的各种方法,包括超速离心、密度梯度离心和免疫亲和层析。作者讨论了外泌体作为各种疾病诊断生物标志物的潜力,以及它们在癌症和其他疾病靶向治疗中的应用。他们还强调了与基于外泌体的疗法相关的挑战,包括需要提高对外泌体生物学的理解和开发标准化制造工艺(5 级)。
Kang et al. [23] explores the potential of exosomes as theragnostics in various clinical situations. The author discusses the role of exosomes in diagnostics, particularly in the
Kang等[23]探讨了外泌体在各种临床情况下作为治疗药物的潜力。作者讨论了外泌体在诊断中的作用,特别是在

detection of biomarkers for cancer and other diseases. They also highlight the potential of exosomes as therapeutic agents, including their use in targeted therapy for cancer and other diseases. The author reviews the current state of knowledge on exosome-based therapies, including their advantages and limitations, and discusses the challenges associated with their development and translation to clinical practice. Additionally, they highlight the need for further research on the safety and efficacy of exosome-based therapies (Level 5).
检测癌症和其他疾病的生物标志物。他们还强调了外泌体作为治疗剂的潜力,包括它们在癌症和其他疾病的靶向治疗中的应用。作者回顾了基于外泌体的疗法的知识现状,包括其优点和局限性,并讨论了与它们的开发和转化为临床实践相关的挑战。此外,它们还强调了进一步研究基于外泌体的疗法的安全性和有效性的必要性(5 级)。
Table 1 provides a summary of the chemical properties of exosomes.
表 1 提供了外泌体化学性质的总结。

Table 1. Key points and classification of the chemical properties of exosomes.
表 1.外泌体化学性质的要点和分类。
Authors 作者 Focus 重点 Key Points 要点 Conclusion 结论 Evidence Level 证据水平
Hu et al. [13] 胡等 [13] Clinical applications of exosome membrane proteins.
外泌体膜蛋白的临床应用。
Importance in disease diagnosis, prognosis, and treatment. Potential as biomarkers.
在疾病诊断、预后和治疗中的重要性。可能作为生物标志物。
Further research needed to understand benefits and risks.
需要进一步的研究来了解益处和风险。
5
Santos, Almeida [14] 阿尔梅达·桑托斯 [14] Development of exosome-based vaccines.
基于外泌体的疫苗的开发。
Advantages as vaccine carriers. Ongoing clinical trials for various diseases.
作为疫苗载体的优势。正在进行的各种疾病的临床试验。
Promising results, but further research needed.
有希望的结果,但还需要进一步的研究。
3b
Song et al. [15] Song等[15] Emerging role of exosomes as therapeutics.
外泌体作为治疗剂的新兴作用。
Biology, isolation, purification, and clinical applications.
生物学、分离、纯化和临床应用。
Advantages and challenges discussed.
讨论了优势和挑战。
5
Wang et al. [17] Wang等[17] Progress in exosome research.
外泌体研究进展。
Isolation, characterization, and clinical applications.
分离、表征和临床应用。
Need for standardized methods and the addressing of contamination issues.
需要标准化方法和解决污染问题。
5
Zhang et al. [22] Zhang等[22] Exosomes in diagnosis and targeted therapy.
外泌体在诊断和靶向治疗中的应用。
Classification, isolation techniques, storage, diagnostic biomarkers, and targeted therapy.
分类、分离技术、储存、诊断生物标志物和靶向治疗。
Challenges in understanding biology and in standardizing processes.
理解生物学和标准化流程的挑战。
5
Kang et al. [23] Kang等[23] Exosomes as theragnostics.
外泌体作为治疗药物。
Role in diagnostics, therapeutic agents, advantages, and limitations.
在诊断、治疗剂、优势和局限性中的作用。
Further research needed for safety and efficacy.
安全性和有效性需要进一步研究。
5
Das et al. [20] Das等[20] Exosomes as a delivery platform for therapeutics.
外泌体作为治疗药物的递送平台。
Unique features: crossing membranes, immune evasion, and targeting cells.
独特功能:跨膜、免疫逃逸和靶向细胞。
Challenges in standardization and scalability.
标准化和可扩展性方面的挑战。
3b
Gurunathan et al. [21] Gurunathan等[21] Exosome biogenesis, functions, and therapeutic applications.
外泌体生物发生、功能和治疗应用。
Factors influencing biogenesis, cellular communication, and therapeutic uses.
影响生物发生、细胞通讯和治疗用途的因素。
Challenges in isolation and purification, and a need for further research.
分离和纯化方面的挑战,以及进一步研究的必要性。
3b
Donoso-Quezada et al. [19]
Donoso-Quezada 等 [19]
Exosome loading and functionalization techniques.
外泌体加载和功能化技术。
Methods for loading therapeutic molecules and recent advancements.
加载治疗分子的方法和最新进展。
Importance of molecular mechanisms and challenges in therapies.
分子机制的重要性和治疗中的挑战。
2c
Aheget et al. [16] Aheget等[16] Exosomes in translational nanomedicine.
转化纳米医学中的外泌体。
Unique characteristics, biocompatibility, and targeted delivery.
独特的特性、生物相容性和靶向递送。
Challenges in isolation, purification, and potential immune rejection.
分离、纯化和潜在免疫排斥方面的挑战。
5
Hood, Wickline [18] 胡德,威克林 [18] Exosome-based translational nanomedicine.
基于外泌体的转化纳米医学。
Delivery platform for siRNAs, miRNAs, and proteins.
siRNA、miRNA 和蛋白质的递送平台。
Challenges in standardization, immune recognition, and clearance.
标准化、免疫识别和清除方面的挑战。
5
Authors Focus Key Points Conclusion Evidence Level Hu et al. [13] Clinical applications of exosome membrane proteins. Importance in disease diagnosis, prognosis, and treatment. Potential as biomarkers. Further research needed to understand benefits and risks. 5 Santos, Almeida [14] Development of exosome-based vaccines. Advantages as vaccine carriers. Ongoing clinical trials for various diseases. Promising results, but further research needed. 3b Song et al. [15] Emerging role of exosomes as therapeutics. Biology, isolation, purification, and clinical applications. Advantages and challenges discussed. 5 Wang et al. [17] Progress in exosome research. Isolation, characterization, and clinical applications. Need for standardized methods and the addressing of contamination issues. 5 Zhang et al. [22] Exosomes in diagnosis and targeted therapy. Classification, isolation techniques, storage, diagnostic biomarkers, and targeted therapy. Challenges in understanding biology and in standardizing processes. 5 Kang et al. [23] Exosomes as theragnostics. Role in diagnostics, therapeutic agents, advantages, and limitations. Further research needed for safety and efficacy. 5 Das et al. [20] Exosomes as a delivery platform for therapeutics. Unique features: crossing membranes, immune evasion, and targeting cells. Challenges in standardization and scalability. 3b Gurunathan et al. [21] Exosome biogenesis, functions, and therapeutic applications. Factors influencing biogenesis, cellular communication, and therapeutic uses. Challenges in isolation and purification, and a need for further research. 3b Donoso-Quezada et al. [19] Exosome loading and functionalization techniques. Methods for loading therapeutic molecules and recent advancements. Importance of molecular mechanisms and challenges in therapies. 2c Aheget et al. [16] Exosomes in translational nanomedicine. Unique characteristics, biocompatibility, and targeted delivery. Challenges in isolation, purification, and potential immune rejection. 5 Hood, Wickline [18] Exosome-based translational nanomedicine. Delivery platform for siRNAs, miRNAs, and proteins. Challenges in standardization, immune recognition, and clearance. 5| Authors | Focus | Key Points | Conclusion | Evidence Level | | :---: | :---: | :---: | :---: | :---: | | Hu et al. [13] | Clinical applications of exosome membrane proteins. | Importance in disease diagnosis, prognosis, and treatment. Potential as biomarkers. | Further research needed to understand benefits and risks. | 5 | | Santos, Almeida [14] | Development of exosome-based vaccines. | Advantages as vaccine carriers. Ongoing clinical trials for various diseases. | Promising results, but further research needed. | 3b | | Song et al. [15] | Emerging role of exosomes as therapeutics. | Biology, isolation, purification, and clinical applications. | Advantages and challenges discussed. | 5 | | Wang et al. [17] | Progress in exosome research. | Isolation, characterization, and clinical applications. | Need for standardized methods and the addressing of contamination issues. | 5 | | Zhang et al. [22] | Exosomes in diagnosis and targeted therapy. | Classification, isolation techniques, storage, diagnostic biomarkers, and targeted therapy. | Challenges in understanding biology and in standardizing processes. | 5 | | Kang et al. [23] | Exosomes as theragnostics. | Role in diagnostics, therapeutic agents, advantages, and limitations. | Further research needed for safety and efficacy. | 5 | | Das et al. [20] | Exosomes as a delivery platform for therapeutics. | Unique features: crossing membranes, immune evasion, and targeting cells. | Challenges in standardization and scalability. | 3b | | Gurunathan et al. [21] | Exosome biogenesis, functions, and therapeutic applications. | Factors influencing biogenesis, cellular communication, and therapeutic uses. | Challenges in isolation and purification, and a need for further research. | 3b | | Donoso-Quezada et al. [19] | Exosome loading and functionalization techniques. | Methods for loading therapeutic molecules and recent advancements. | Importance of molecular mechanisms and challenges in therapies. | 2c | | Aheget et al. [16] | Exosomes in translational nanomedicine. | Unique characteristics, biocompatibility, and targeted delivery. | Challenges in isolation, purification, and potential immune rejection. | 5 | | Hood, Wickline [18] | Exosome-based translational nanomedicine. | Delivery platform for siRNAs, miRNAs, and proteins. | Challenges in standardization, immune recognition, and clearance. | 5 |

3. Extraction and Clinical Uses of Exosomes
3. 外泌体的提取和临床应用

Mendt, Rezvani, and Shpall [24] discuss the potential use of mesenchymal stem cellderived exosomes (MSC-Exos) as a therapeutic agent for various diseases. The authors highlight the benefits of MSC-Exos, including their ability to promote tissue repair and regeneration, modulate immune responses, and deliver therapeutic cargo. They also discuss the challenges and uncertainties associated with the use of MSC-Exos, including the need for standardized methods for isolating and purifying exosomes, as well as the potential risks associated with their use. The authors conclude that further research is needed to fully understand the potential benefits and risks of MSC-Exos and to optimize their use as a therapeutic agent (Level 4).
Mendt、Rezvani 和 Shpall [24] 讨论了间充质干细胞衍生外泌体 (MSC-Exos) 作为各种疾病治疗剂的潜在用途。作者强调了 MSC-Exos 的好处,包括它们促进组织修复和再生、调节免疫反应和递送治疗货物的能力。他们还讨论了与使用 MSC-Exos 相关的挑战和不确定性,包括分离和纯化外泌体的标准化方法的必要性,以及与其使用相关的潜在风险。作者得出结论,需要进一步的研究来充分了解 MSC-Exos 的潜在益处和风险,并优化其作为治疗剂的使用(第 4 级)。
Perocheau et al. [25] discusses the current state of clinical applications for exosomes, highlighting their potential as therapeutic agents for various diseases. The authors review the existing evidence for exosomes in treating cardiovascular disease, cancer, and neurological disorders. They also discuss the challenges and limitations associated with the use of exosomes, including their isolation, purification, and characterization. The authors
Perocheau 等 [25] 讨论了外泌体临床应用的现状,强调了它们作为各种疾病治疗剂的潜力。作者回顾了外泌体治疗心血管疾病、癌症和神经系统疾病的现有证据。他们还讨论了与使用外泌体相关的挑战和限制,包括它们的分离、纯化和表征。作者

conclude that while significant progress has been made in understanding the biology of exosomes, further research is needed to fully elucidate their clinical potential (Level 3a).
结论是,虽然在了解外泌体的生物学方面取得了重大进展,但需要进一步的研究来充分阐明它们的临床潜力(3a 级)。
The paper by Rezaie et al. [26] provides a comprehensive review of the current state of exosome-based therapies in clinical trials, highlighting their potential and challenges. The authors discuss the various ways exosomes are being used in clinical trials, including their application as therapeutic agents for cancer, autoimmune disorders, and infectious diseases. They also examine the challenges and limitations associated with exosome-based therapies, including their isolation, purification, and characterization. The authors emphasize the need for further research to address these challenges and improve the efficacy and safety of exosome-based therapies (Level 5).
Rezaie等[26]的论文全面回顾了临床试验中基于外泌体的疗法的现状,强调了它们的潜力和挑战。作者讨论了外泌体在临床试验中的各种使用方式,包括它们作为癌症、自身免疫性疾病和传染病治疗剂的应用。他们还研究了与基于外泌体的疗法相关的挑战和局限性,包括它们的分离、纯化和表征。作者强调需要进一步研究来应对这些挑战并提高基于外泌体的疗法的有效性和安全性(5 级)。
Urbanelli et al. [27] reviews the potential of exosomes as a novel approach for diagnosis and therapy. The authors discuss the role of exosomes in various biological processes, including cellular communication and immune response. They highlight the advantages of exosomes as diagnostic tools, including their ability to detect specific biomarkers and provide real-time information on disease progression. The authors also explore the therapeutic potential of exosomes, including their use as vehicles for targeted drug delivery and gene therapy. They discuss the challenges and limitations associated with exosome-based strategies, including their isolation, purification, and characterization (Level 5).
Urbanelli 等 [27] 回顾了外泌体作为诊断和治疗新方法的潜力。作者讨论了外泌体在各种生物过程中的作用,包括细胞通讯和免疫反应。他们强调了外泌体作为诊断工具的优势,包括它们检测特定生物标志物和提供有关疾病进展的实时信息的能力。作者还探讨了外泌体的治疗潜力,包括它们作为靶向药物递送和基因治疗的载体。他们讨论了与基于外泌体的策略相关的挑战和局限性,包括它们的分离、纯化和表征(第 5 级)。
Cully [28] highlights the progress of exosome-based therapies in moving into clinical trials. The author notes that several exosome-based candidates have entered clinical trials, with a focus on treating cancer, autoimmune diseases, and neurological disorders. The author also discusses the advantages of exosomes as therapeutic agents, including their ability to deliver specific biomarkers and modulate immune responses. Additionally, the author mentions the challenges and limitations associated with exosome-based therapies, including issues with scalability, purity, and stability (Level 1b).
Cully [28] 强调了基于外泌体的疗法在进入临床试验方面的进展。作者指出,几种基于外泌体的候选药物已进入临床试验,重点是治疗癌症、自身免疫性疾病和神经系统疾病。作者还讨论了外泌体作为治疗剂的优势,包括它们传递特异性生物标志物和调节免疫反应的能力。此外,作者还提到了与基于外泌体的疗法相关的挑战和局限性,包括可扩展性、纯度和稳定性(1b 级)问题。
Batrakova and Kim [29] focus on the development and regulation of exosome-based therapy products. The authors discuss the current understanding of exosomes and their potential as therapeutic agents, highlighting their ability to deliver biomarkers, modulate immune responses, and treat various diseases. The authors also provide an overview of the regulatory framework for exosome-based therapies, including the challenges and limitations associated with their development and approval. They discuss the need for the standardization and validation of exosome-based products, as well as the importance of understanding the biological mechanisms underlying exosome-mediated delivery (Level 2b).
Batrakova 和 Kim [29] 专注于基于外泌体的治疗产品的开发和调节。作者讨论了目前对外泌体及其作为治疗剂的潜力的理解,强调了它们递送生物标志物、调节免疫反应和治疗各种疾病的能力。作者还概述了基于外泌体的疗法的监管框架,包括与其开发和批准相关的挑战和限制。他们讨论了基于外泌体的产品标准化和验证的必要性,以及了解外泌体介导的递送(2b 级)的生物学机制的重要性。
Harrell et al. [30] provides an overview of the therapeutic potential of exosomes derived from mesenchymal stem cells (MSCs). The authors discuss the current understanding of exosomes, their biology, and their ability to deliver therapeutic cargo to target cells. They highlight the benefits of using MSC-derived exosomes, including their immunomodulatory and anti-inflammatory properties, as well as their potential to treat various diseases such as cardiovascular disease, neurological disorders, and cancer. The authors also summarize the current state of clinical trials and regulatory frameworks for exosome-based therapies, emphasizing the need for further research to address the challenges and limitations associated with their translation into clinical practice (Level 5).
Harrell等[30]概述了间充质干细胞(MSCs)来源的外泌体的治疗潜力。作者讨论了目前对外泌体、其生物学特性及其向靶细胞输送治疗货物的能力的理解。他们强调了使用 MSC 衍生外泌体的好处,包括它们的免疫调节和抗炎特性,以及它们治疗各种疾病(如心血管疾病、神经系统疾病和癌症)的潜力。作者还总结了基于外泌体的疗法的临床试验和监管框架的现状,强调需要进一步研究来解决与将其转化为临床实践相关的挑战和限制(第 5 级)。
The paper by Lee et al. [31] provides an overview of the therapeutic features and clinical trials of mesenchymal stem cell (MSC)-derived exosomes. The authors discuss the composition and functions of MSC-derived exosomes, highlighting their potential for therapeutic applications in various diseases, including cardiovascular, neurological, and inflammatory disorders. They review the current state of MSC-derived exosomebased therapies in preclinical studies and clinical trials, focusing on their mechanisms of action, safety, and efficacy. The authors also highlight the challenges and limitations of MSC-derived exosome-based therapies, emphasizing the need for further research to fully understand their potential and address these limitations (Level 1c).
Lee 等 [31] 的论文概述了间充质干细胞 (MSC) 来源的外泌体的治疗特性和临床试验。作者讨论了 MSC 来源的外泌体的组成和功能,强调了它们在各种疾病(包括心血管、神经和炎症性疾病)中的治疗应用潜力。他们回顾了临床前研究和临床试验中基于 MSC 衍生的外泌体疗法的现状,重点关注其作用机制、安全性和有效性。作者还强调了 MSC 衍生的基于外泌体的疗法的挑战和局限性,强调需要进一步研究以充分了解其潜力并解决这些局限性(1c 级)。
Chen et al. [32] reviews the current state of exosomes in clinical trials, focusing on their production and compliance with good manufacturing practice (GMP). The authors discuss the challenges and limitations of exosome production, including the need for standardized
Chen等[32]回顾了外泌体在临床试验中的现状,重点介绍了其生产和符合药品生产质量管理规范(GMP)的情况。作者讨论了外泌体生产的挑战和局限性,包括标准化的必要性

methods and quality control. They highlight the importance of GMP-compliant production to ensure the safety and efficacy of exosome-based therapies. The review also discusses the current regulatory landscape and the potential for exosomes to be used as a new therapeutic platform. The authors conclude that while there are still challenges to be overcome, the development of GMP-compliant exosome production methods holds promise for the future of exosome-based therapies (Level 3b).
方法和质量控制。它们强调了符合 GMP 的生产对于确保基于外泌体的疗法的安全性和有效性的重要性。该综述还讨论了当前的监管环境以及外泌体用作新治疗平台的潜力。作者得出结论,虽然仍有挑战需要克服,但符合 GMP 的外泌体生产方法的开发为基于外泌体的疗法(3b 级)的未来带来了希望。
Lotfy et al. [33] reviews the current status of clinical trials involving mesenchymal stromal/stem cell (MSC)-derived exosomes. The authors summarize the results of 14 clinical trials which investigated the use of MSC-derived exosomes as a treatment for various diseases, including cardiovascular disease, graft-versus-host disease, and inflammatory bowel disease. The authors highlight the potential benefits of exosomes, including their ability to promote tissue repair and modulate the immune response. They also discuss the challenges and limitations of exosome therapy, including the need for the standardization of exosome production and purification methods. The authors conclude that MSC-derived exosomes show promise as a therapeutic agent, but further research is needed to fully understand their efficacy and potential (Level 2b).
Lotfy等[33]回顾了涉及间充质基质/干细胞(MSC)衍生外泌体的临床试验的现状。作者总结了 14 项临床试验的结果,这些试验调查了使用 MSC 衍生的外泌体治疗各种疾病,包括心血管疾病、移植物抗宿主病和炎症性肠病。作者强调了外泌体的潜在好处,包括它们促进组织修复和调节免疫反应的能力。他们还讨论了外泌体治疗的挑战和局限性,包括外泌体生产和纯化方法标准化的必要性。作者得出结论,MSC 衍生的外泌体显示出作为治疗剂的前景,但需要进一步研究以充分了解其疗效和潜力(2b 级)。
Table 2 provides a summary of the extraction and clinical uses of exosomes.
表 2 总结了外泌体的提取和临床应用。

Table 2. Key points and classification of the extraction and clinical uses of exosomes.
表 2.外泌体提取和临床应用的要点和分类。
Authors 作者 Focus 重点 Key Points 要点 Conclusion 结论 Evidence Level 证据水平
Mendt, Rezvani, Shpall [24]
Mendt, Rezvani, Shpall [24]
MSC-derived exosomes as therapeutic agents.
MSC 衍生的外泌体作为治疗剂。
Benefits: tissue repair, immune modulation, and therapeutic delivery. Challenges: standardization, and risks.
好处:组织修复、免疫调节和治疗递送。挑战:标准化和风险。
Further research needed to optimize usage and to understand the risks.
需要进一步的研究来优化使用并了解风险。
4
Perocheau et al. [25] Perocheau 等 [25] Clinical applications of exosomes.
外泌体的临床应用。
Potential in treating cardiovascular disease, cancer, and neurological disorders.
在治疗心血管疾病、癌症和神经系统疾病方面的潜力。
Further research needed to understand the clinical potential.
需要进一步的研究来了解临床潜力。
3a
Rezaie et al. [26] Rezaie等[26] Exosome-based therapies in clinical trials.
临床试验中基于外泌体的疗法。
Applications in cancer, autoimmune disorders, and infectious diseases.
应用于癌症、自身免疫性疾病和传染病。
Need for further research to improve efficacy and safety.
需要进一步研究以提高疗效和安全性。
5
Batrakova, Kim [29] 金·巴特拉科娃 [29] Development and regulation of exosome therapy products.
外泌体治疗产品的开发和监管。
Understanding, regulation, standardization, and validation of exosome-based products.
基于外泌体的产品的理解、监管、标准化和验证。
Need for further research on the biological mechanisms.
需要进一步研究其生物学机制。
2b
Harrell et al. [30] Harrell等[30] Therapeutic potential of MSC-derived exosomes.
MSC 衍生外泌体的治疗潜力。
Immunomodulatory, anti-inflammatory properties, and treating various diseases.
免疫调节、抗炎特性和治疗各种疾病。
Need for further research on clinical trials and regulatory frameworks.
需要对临床试验和监管框架进行进一步研究。
5
Lee et al. [31] Lee等[31] MSC-derived exosome therapies.
MSC 来源的外泌体疗法。
Therapeutic applications, mechanisms, safety, and efficacy.
治疗应用、机制、安全性和疗效。
Challenges and limitations emphasized.
强调挑战和限制。
1c
Lotfy et al. [33] Lotfy等[33] MSC-derived exosomes in clinical trials.
临床试验中的 MSC 衍生外泌体。
Treating cardiovascular disease, GVHD, and inflammatory bowel disease.
治疗心血管疾病、GVHD 和炎症性肠病。
Need for standardization in production and purification methods.
生产和纯化方法需要标准化。
2b
Chen et al. [32] Chen等[32] Exosomes in clinical trials.
临床试验中的外泌体。
Production, compliance with GMP, and the regulatory landscape.
生产、GMP 合规性和监管环境。
Promising future, with challenges to overcome.
充满希望的未来,也有需要克服的挑战。
3b
Urbanelli et al. [27] Urbanelli等[27] Exosomes for diagnosis and therapy.
用于诊断和治疗的外泌体。
Advantages as diagnostic tools and therapeutic vehicles.
作为诊断工具和治疗工具的优势。
Challenges in isolation, purification, and characterization.
分离、纯化和表征方面的挑战。
5
Cully et al. [28] Cully等[28] Exosome-based therapies in clinical trials.
临床试验中基于外泌体的疗法。
Treating cancer, autoimmune diseases, and neurological disorders.
治疗癌症、自身免疫性疾病和神经系统疾病。
Advantages and challenges discussed.
讨论了优势和挑战。
1b
Authors Focus Key Points Conclusion Evidence Level Mendt, Rezvani, Shpall [24] MSC-derived exosomes as therapeutic agents. Benefits: tissue repair, immune modulation, and therapeutic delivery. Challenges: standardization, and risks. Further research needed to optimize usage and to understand the risks. 4 Perocheau et al. [25] Clinical applications of exosomes. Potential in treating cardiovascular disease, cancer, and neurological disorders. Further research needed to understand the clinical potential. 3a Rezaie et al. [26] Exosome-based therapies in clinical trials. Applications in cancer, autoimmune disorders, and infectious diseases. Need for further research to improve efficacy and safety. 5 Batrakova, Kim [29] Development and regulation of exosome therapy products. Understanding, regulation, standardization, and validation of exosome-based products. Need for further research on the biological mechanisms. 2b Harrell et al. [30] Therapeutic potential of MSC-derived exosomes. Immunomodulatory, anti-inflammatory properties, and treating various diseases. Need for further research on clinical trials and regulatory frameworks. 5 Lee et al. [31] MSC-derived exosome therapies. Therapeutic applications, mechanisms, safety, and efficacy. Challenges and limitations emphasized. 1c Lotfy et al. [33] MSC-derived exosomes in clinical trials. Treating cardiovascular disease, GVHD, and inflammatory bowel disease. Need for standardization in production and purification methods. 2b Chen et al. [32] Exosomes in clinical trials. Production, compliance with GMP, and the regulatory landscape. Promising future, with challenges to overcome. 3b Urbanelli et al. [27] Exosomes for diagnosis and therapy. Advantages as diagnostic tools and therapeutic vehicles. Challenges in isolation, purification, and characterization. 5 Cully et al. [28] Exosome-based therapies in clinical trials. Treating cancer, autoimmune diseases, and neurological disorders. Advantages and challenges discussed. 1b| Authors | Focus | Key Points | Conclusion | Evidence Level | | :---: | :---: | :---: | :---: | :---: | | Mendt, Rezvani, Shpall [24] | MSC-derived exosomes as therapeutic agents. | Benefits: tissue repair, immune modulation, and therapeutic delivery. Challenges: standardization, and risks. | Further research needed to optimize usage and to understand the risks. | 4 | | Perocheau et al. [25] | Clinical applications of exosomes. | Potential in treating cardiovascular disease, cancer, and neurological disorders. | Further research needed to understand the clinical potential. | 3a | | Rezaie et al. [26] | Exosome-based therapies in clinical trials. | Applications in cancer, autoimmune disorders, and infectious diseases. | Need for further research to improve efficacy and safety. | 5 | | Batrakova, Kim [29] | Development and regulation of exosome therapy products. | Understanding, regulation, standardization, and validation of exosome-based products. | Need for further research on the biological mechanisms. | 2b | | Harrell et al. [30] | Therapeutic potential of MSC-derived exosomes. | Immunomodulatory, anti-inflammatory properties, and treating various diseases. | Need for further research on clinical trials and regulatory frameworks. | 5 | | Lee et al. [31] | MSC-derived exosome therapies. | Therapeutic applications, mechanisms, safety, and efficacy. | Challenges and limitations emphasized. | 1c | | Lotfy et al. [33] | MSC-derived exosomes in clinical trials. | Treating cardiovascular disease, GVHD, and inflammatory bowel disease. | Need for standardization in production and purification methods. | 2b | | Chen et al. [32] | Exosomes in clinical trials. | Production, compliance with GMP, and the regulatory landscape. | Promising future, with challenges to overcome. | 3b | | Urbanelli et al. [27] | Exosomes for diagnosis and therapy. | Advantages as diagnostic tools and therapeutic vehicles. | Challenges in isolation, purification, and characterization. | 5 | | Cully et al. [28] | Exosome-based therapies in clinical trials. | Treating cancer, autoimmune diseases, and neurological disorders. | Advantages and challenges discussed. | 1b |

4. Exosomes in Disease Treatment and Regenerative Medicine
4. 外泌体在疾病治疗和再生医学中的应用

Chung et al. [34] provide an overview of the current uses and future applications of exosomes. The authors discuss the role of exosomes in disease diagnosis, prognosis, and treatment, highlighting their potential as biomarkers for various diseases. They also review the use of exosomes as therapeutic agents, including their ability to deliver therapeutic cargo and modulate immune responses. The authors explore the potential applications of exosomes in regenerative medicine, cancer therapy, and gene therapy. Additionally, they discuss the challenges and limitations associated with the use of exosomes, including their isolation, purification, and characterization (Level 5).
Chung等[34]概述了外泌体的当前用途和未来应用。作者讨论了外泌体在疾病诊断、预后和治疗中的作用,强调了它们作为各种疾病生物标志物的潜力。他们还回顾了外泌体作为治疗剂的使用,包括它们传递治疗货物和调节免疫反应的能力。作者探讨了外泌体在再生医学、癌症治疗和基因治疗中的潜在应用。此外,他们还讨论了与使用外泌体相关的挑战和限制,包括它们的分离、纯化和表征(5 级)。
Vitha et al. [35] explore the potential of exosomes in orthopedics. The authors provide an overview of exosomes, their biogenesis, and their characteristics. They highlight the therapeutic applications of exosomes in orthopedic disorders, including their ability to deliver bioactive molecules, modulate immune responses, and promote tissue repair. The authors discuss the potential uses of exosomes in treating conditions such as osteoarthritis, osteoporosis, and tendon injuries. They also review the current state of exosome-based therapies in preclinical studies and clinical trials, emphasizing the need for further research to fully understand their mechanisms and potential (Level 2c).
Vitha等[35]探讨了外泌体在骨科中的潜力。作者概述了外泌体、它们的生物发生和它们的特性。他们强调了外泌体在骨科疾病中的治疗应用,包括它们递送生物活性分子、调节免疫反应和促进组织修复的能力。作者讨论了外泌体在治疗骨关节炎、骨质疏松症和肌腱损伤等疾病方面的潜在用途。他们还回顾了临床前研究和临床试验中基于外泌体的疗法的现状,强调需要进一步研究以充分了解其机制和潜力(2c 级)。
Popowski et al. [36] discuss the potential of exosomes in lung regenerative medicine. The authors provide an overview of exosomes, their biogenesis, and their therapeutic applications. They highlight the benefits of using exosomes, including their ability to deliver therapeutic cargo, modulate immune responses, and promote tissue repair. The authors focus on the use of exosomes for treating lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer. They review the current state of exosome-based therapies in preclinical studies and clinical trials, emphasizing the need for further research to fully understand their mechanisms (Level 2b).
Popowski 等 [36] 讨论了外泌体在肺再生医学中的潜力。作者概述了外泌体、它们的生物发生和它们的治疗应用。他们强调了使用外泌体的好处,包括它们传递治疗货物、调节免疫反应和促进组织修复的能力。作者专注于使用外泌体治疗肺部疾病,如慢性阻塞性肺病 (COPD)、肺纤维化和肺癌。他们回顾了临床前研究和临床试验中基于外泌体的疗法的现状,强调需要进一步研究以充分了解其机制(2b 级)。
Sanghani et al. [37] review the current state of exosome therapies in ophthalmology, highlighting their potential applications in treating various eye diseases. The authors discuss the basic science and preclinical studies that have demonstrated the therapeutic potential of exosomes in ophthalmology, including their ability to deliver therapeutic cargo, modulate immune responses, and promote tissue repair. They also review the current clinical trials and case reports that have used exosomes to treat various ophthalmic disorders, such as age-related macular degeneration, diabetic retinopathy, and glaucoma. The authors emphasize the need for further research to fully understand the mechanisms of action and efficacy of exosome therapies in ophthalmology (Level 2c).
Sanghani等[37]回顾了外泌体疗法在眼科领域的现状,强调了它们在治疗各种眼病方面的潜在应用。作者讨论了已经证明外泌体在眼科治疗潜力的基础科学和临床前研究,包括它们传递治疗货物、调节免疫反应和促进组织修复的能力。他们还回顾了目前使用外泌体治疗各种眼科疾病的临床试验和病例报告,例如年龄相关性黄斑变性、糖尿病性视网膜病变和青光眼。作者强调需要进一步研究,以充分了解外泌体疗法在眼科 (2c 级) 中的作用机制和疗效。
Kost et al. [38] provide a comprehensive review of the current state of exosome therapy in hair regeneration. The authors summarize the existing literature on the use of exosomes as a potential treatment for hair loss, including their potential mechanisms of action, such as stimulating hair growth and improving hair follicle function. They highlight the benefits of exosomes, including their ability to target specific cells and tissues, and their potential for reducing side effects. The authors also discuss the challenges and limitations of exosome therapy, including the need for standardization of exosome production and purification methods. They conclude that while exosome therapy shows promise for hair regeneration, further research is needed to fully understand its efficacy and potential (Level 2c).
Kost等[38]对外泌体疗法在头发再生中的现状进行了全面综述。作者总结了关于使用外泌体作为脱发潜在治疗方法的现有文献,包括它们的潜在作用机制,例如刺激头发生长和改善毛囊功能。他们强调了外泌体的好处,包括它们靶向特定细胞和组织的能力,以及它们减少副作用的潜力。作者还讨论了外泌体治疗的挑战和局限性,包括外泌体生产和纯化方法标准化的必要性。他们得出的结论是,虽然外泌体疗法显示出头发再生的希望,但需要进一步的研究来充分了解其疗效和潜力(2c 级)。
Kavya et al. [39] provide a comprehensive review of the therapeutic applications of exosomes in various diseases. The authors summarize the existing literature on the use of exosomes as a potential treatment for various diseases, including cancer, cardiovascular disease, neurological disorders, and infectious diseases. They highlight the potential benefits of exosomes, including their ability to deliver therapeutic molecules, modulate the immune response, and promote tissue repair. The authors also discuss the challenges and limitations of exosome therapy, including the need for standardization of exosome production and purification methods. They conclude that exosomes have great potential for treating various diseases, but further research is needed to fully understand their efficacy and potential (Level 1c).
Kavya等[39]全面综述了外泌体在各种疾病中的治疗应用。作者总结了关于使用外泌体作为各种疾病潜在治疗方法的现有文献,包括癌症、心血管疾病、神经系统疾病和传染病。他们强调了外泌体的潜在好处,包括它们递送治疗分子、调节免疫反应和促进组织修复的能力。作者还讨论了外泌体治疗的挑战和局限性,包括外泌体生产和纯化方法标准化的必要性。他们得出的结论是,外泌体在治疗各种疾病方面具有巨大潜力,但需要进一步研究以充分了解它们的疗效和潜力(1c 级)。
Salarpour et al. [40] reviews the potential of exosomes and exosome-nanoparticle complexes for treating brain disorders. The authors discuss the unique features of exosomes, including their ability to cross the blood-brain barrier and deliver therapeutic agents to specific brain regions. They highlight the potential benefits of using exosomes as a targeted delivery system for brain disorders, including Alzheimer’s disease, Parkinson’s disease, and stroke. The authors also review the current state of research on exosomenanoparticle complexes, which combine the targeting capabilities of exosomes with the enhanced delivery efficiency of nanoparticles. They conclude that further research is needed to fully understand the potential of exosomes and exosome-nanoparticle complexes for treating brain disorders (Level 1b).
Salarpour等[40]综述了外泌体和外泌体-纳米颗粒复合物治疗脑部疾病的潜力。作者讨论了外泌体的独特特征,包括它们穿过血脑屏障并将治疗剂输送到特定大脑区域的能力。他们强调了使用外泌体作为脑部疾病(包括阿尔茨海默病、帕金森病和中风)靶向递送系统的潜在好处。作者还回顾了外泌体纳米颗粒复合物的研究现状,该复合物结合了外泌体的靶向能力与纳米颗粒增强的递送效率。他们得出的结论是,需要进一步的研究来充分了解外泌体和外泌体-纳米颗粒复合物治疗脑部疾病(1b 级)的潜力。
Table 3 provides a summary of the exosomes in disease treatment and regenerative medicine.
表 3 总结了外泌体在疾病治疗和再生医学中的应用。

Table 3. Key points and classification of the exosomes in disease treatment and regenerative medicine.
表 3.外泌体在疾病治疗和再生医学中的关键点和分类。
Authors 作者 Focus 重点 Key Points 要点 Conclusion 结论 Evidence Level 证据水平
Chung et al. [34] Chung等[34] Current uses and future applications of exosomes.
外泌体的当前用途和未来应用。
Role in diagnosis, prognosis, treatment, regenerative medicine, cancer therapy, and gene therapy.
在诊断、预后、治疗、再生医学、癌症治疗和基因治疗中的作用。
Challenges in isolation, purification, and characterization.
分离、纯化和表征方面的挑战。
5
Vitha et al. [35] Vitha等[35] Exosomes in orthopedics. 骨科中的外泌体。 Delivering bioactive molecules, modulating immune responses, and promoting tissue repair.
递送生物活性分子,调节免疫反应,促进组织修复。
Further research needed to understand the mechanisms and potential.
需要进一步的研究来了解其机制和潜力。
2c
Popowski et al. [36] Popowski等[36] Exosomes in lung regenerative medicine.
肺再生医学中的外泌体。
Treating COPD, pulmonary fibrosis, and lung cancer.
治疗 COPD、肺纤维化和肺癌。
Further research needed to understand the mechanisms.
需要进一步的研究来了解其机制。
2b
Sanghani et al. [37] Sanghani 等 [37] Exosome therapies in ophthalmology.
眼科外泌体疗法。
Treating eye diseases and promoting tissue repair.
治疗眼病,促进组织修复。
Need for further research on the mechanisms and efficacy.
需要进一步研究机制和疗效。
2c
Kavya et al. [39] Kavya等[39] Therapeutic applications of exosomes.
外泌体的治疗应用。
Potential in treating cancer, cardiovascular disease, neurological disorders, and infectious diseases.
在治疗癌症、心血管疾病、神经系统疾病和传染病方面的潜力。
Challenges in standardization and efficacy.
标准化和有效性方面的挑战。
1c
Kost et al. [38] Kost等[38] Exosome therapy in hair regeneration.
头发再生中的外泌体疗法。
Stimulating hair growth and improving follicle function.
刺激头发生长,改善毛囊功能。
Need for standardization in production and purification methods.
生产和纯化方法需要标准化。
2c
Willis et al. [41] Willis等[41] Exosomes in cardiovascular disease therapy.
心血管疾病治疗中的外泌体。
Challenges in development, heterogeneity, and understanding biological functions.
发育、异质性和理解生物学功能方面的挑战。
Need for research on fit-for-purpose potency.
需要研究适合目的的效力。
2c
Salarpour et al. [40] Salarpour等[40] Exosomes and nanoparticle complexes for brain disorders.
用于脑部疾病的外泌体和纳米颗粒复合物。
Crossing the blood-brain barrier, targeted delivery for Alzheimer's, Parkinson's, and stroke.
穿越血脑屏障,针对阿尔茨海默氏症、帕金森氏症和中风的靶向递送。
Further research needed to understand potential.
需要进一步的研究来了解潜力。
1b
Authors Focus Key Points Conclusion Evidence Level Chung et al. [34] Current uses and future applications of exosomes. Role in diagnosis, prognosis, treatment, regenerative medicine, cancer therapy, and gene therapy. Challenges in isolation, purification, and characterization. 5 Vitha et al. [35] Exosomes in orthopedics. Delivering bioactive molecules, modulating immune responses, and promoting tissue repair. Further research needed to understand the mechanisms and potential. 2c Popowski et al. [36] Exosomes in lung regenerative medicine. Treating COPD, pulmonary fibrosis, and lung cancer. Further research needed to understand the mechanisms. 2b Sanghani et al. [37] Exosome therapies in ophthalmology. Treating eye diseases and promoting tissue repair. Need for further research on the mechanisms and efficacy. 2c Kavya et al. [39] Therapeutic applications of exosomes. Potential in treating cancer, cardiovascular disease, neurological disorders, and infectious diseases. Challenges in standardization and efficacy. 1c Kost et al. [38] Exosome therapy in hair regeneration. Stimulating hair growth and improving follicle function. Need for standardization in production and purification methods. 2c Willis et al. [41] Exosomes in cardiovascular disease therapy. Challenges in development, heterogeneity, and understanding biological functions. Need for research on fit-for-purpose potency. 2c Salarpour et al. [40] Exosomes and nanoparticle complexes for brain disorders. Crossing the blood-brain barrier, targeted delivery for Alzheimer's, Parkinson's, and stroke. Further research needed to understand potential. 1b| Authors | Focus | Key Points | Conclusion | Evidence Level | | :---: | :---: | :---: | :---: | :---: | | Chung et al. [34] | Current uses and future applications of exosomes. | Role in diagnosis, prognosis, treatment, regenerative medicine, cancer therapy, and gene therapy. | Challenges in isolation, purification, and characterization. | 5 | | Vitha et al. [35] | Exosomes in orthopedics. | Delivering bioactive molecules, modulating immune responses, and promoting tissue repair. | Further research needed to understand the mechanisms and potential. | 2c | | Popowski et al. [36] | Exosomes in lung regenerative medicine. | Treating COPD, pulmonary fibrosis, and lung cancer. | Further research needed to understand the mechanisms. | 2b | | Sanghani et al. [37] | Exosome therapies in ophthalmology. | Treating eye diseases and promoting tissue repair. | Need for further research on the mechanisms and efficacy. | 2c | | Kavya et al. [39] | Therapeutic applications of exosomes. | Potential in treating cancer, cardiovascular disease, neurological disorders, and infectious diseases. | Challenges in standardization and efficacy. | 1c | | Kost et al. [38] | Exosome therapy in hair regeneration. | Stimulating hair growth and improving follicle function. | Need for standardization in production and purification methods. | 2c | | Willis et al. [41] | Exosomes in cardiovascular disease therapy. | Challenges in development, heterogeneity, and understanding biological functions. | Need for research on fit-for-purpose potency. | 2c | | Salarpour et al. [40] | Exosomes and nanoparticle complexes for brain disorders. | Crossing the blood-brain barrier, targeted delivery for Alzheimer's, Parkinson's, and stroke. | Further research needed to understand potential. | 1b |
The exosomes can be used in many of the following medical fields (Figure 3).
外泌体可用于以下许多医学领域(图 3)。

Figure 3. The diverse medical applications of exosomes. The arrows represent the various sources and applications of exosomes in different medical fields. The versatile roles of exosomes in advancing medical science offer novel approaches for diagnosis, treatment, and monitoring of various health conditions.
图 3.外泌体的多种医学应用。箭头代表外泌体在不同医学领域的各种来源和应用。外泌体在推进医学科学方面的多功能作用为诊断、治疗和监测各种健康状况提供了新的方法。

5. Exosomes in Diagnostic and Therapeutic Tools
5. 诊断和治疗工具中的外泌体

Huda et al. [42] provide a comprehensive review of the potential uses of exosomes in biomedical applications, including diagnosis and targeted drug delivery. The authors discuss the current state of exosome-based diagnostics, highlighting their ability to detect biomarkers for various diseases, such as cancer, neurological disorders, and infectious diseases. They also explore the therapeutic potential of exosomes, including their use
Huda等[42]全面综述了外泌体在生物医学应用中的潜在用途,包括诊断和靶向药物递送。作者讨论了基于外泌体的诊断的现状,强调了它们检测各种疾病(如癌症、神经系统疾病和传染病)的生物标志物的能力。他们还探索了外泌体的治疗潜力,包括它们的用途

as vehicles for targeted drug delivery and gene therapy. The authors summarize the progress in clinical and preclinical applications, highlighting the challenges and limitations associated with exosome-based therapies (Level 2b).
作为靶向药物递送和基因治疗的载体。作者总结了临床和临床前应用的进展,强调了与基于外泌体的疗法相关的挑战和局限性(2b 级)。
Sun and Liu [43] review the potential of cancer cell-derived exosomes in clinical applications. The authors discuss the role of exosomes in cancer development and progression, as well as their ability to mediate immune evasion and promote tumor growth. They also highlight the recent advances in understanding the biological properties of exosomes, including their composition, isolation, and characterization. The authors review the potential therapeutic applications of cancer cell-derived exosomes, including their use as biomarkers for cancer diagnosis and treatment, as well as their potential for targeted delivery of therapeutic agents. They also discuss the challenges and limitations associated with the use of exosomes in clinical applications, including their heterogeneity and potential for immune rejection (Level 2b).
Sun 和 Liu [43] 回顾了癌细胞衍生的外泌体在临床应用中的潜力。作者讨论了外泌体在癌症发展和进展中的作用,以及它们介导免疫逃逸和促进肿瘤生长的能力。他们还强调了了解外泌体生物学特性的最新进展,包括它们的组成、分离和表征。作者回顾了癌细胞来源的外泌体的潜在治疗应用,包括它们作为癌症诊断和治疗的生物标志物的用途,以及它们靶向递送治疗剂的潜力。他们还讨论了在临床应用中使用外泌体相关的挑战和局限性,包括它们的异质性和免疫排斥的可能性(2b 级)。
Xu et al. [44] review the potential of exosome-based immunotherapy for cancer treatment. The authors discuss the biological properties of exosomes, including their ability to deliver therapeutic agents, such as siRNAs, miRNAs, and proteins, to specific cells. They highlight the advantages of exosome-based immunotherapy, including its potential for targeted delivery, low toxicity, and immune tolerance. The authors review the current preclinical and clinical studies using exosome-based immunotherapy for cancer treatment, including its use in combination with other therapies such as chemotherapy and immunotherapy. They also discuss the challenges and limitations associated with the use of exosome-based immunotherapy, including its potential for immune rejection and the need for improved manufacturing and characterization techniques (Level 2c)
Xu等[44]回顾了基于外泌体的免疫疗法在癌症治疗中的潜力。作者讨论了外泌体的生物学特性,包括它们将治疗剂(如 siRNA、miRNA 和蛋白质)递送到特定细胞的能力。他们强调了基于外泌体的免疫疗法的优势,包括其靶向递送、低毒性和免疫耐受的潜力。作者回顾了目前使用基于外泌体的免疫疗法进行癌症治疗的临床前和临床研究,包括其与其他疗法(如化疗和免疫疗法)的联合使用。他们还讨论了与使用基于外泌体的免疫疗法相关的挑战和局限性,包括其免疫排斥的可能性以及改进制造和表征技术的需求(2c 级)
Zipkin and colleagues [45] provide a comprehensive review of exosomes, their biology, and their potential applications in medicine. The author highlights the recent advancements in exosome research, including their isolation and purification methods and their potential as therapeutic agents. The review also discusses the challenges and limitations associated with exosome research, including the lack of standardization and the need for further understanding of their biology and mechanisms of action. The author also discusses the potential applications of exosomes in various fields, including cancer therapy, regenerative medicine, and vaccine development (Level 5).
Zipkin及其同事[45]对外泌体、它们的生物学特性及其在医学中的潜在应用进行了全面综述。作者强调了外泌体研究的最新进展,包括它们的分离和纯化方法以及它们作为治疗剂的潜力。该综述还讨论了与外泌体研究相关的挑战和局限性,包括缺乏标准化以及需要进一步了解其生物学和作用机制。作者还讨论了外泌体在各个领域的潜在应用,包括癌症治疗、再生医学和疫苗开发(5 级)。
Tai et al. [46] reviews the current understanding of exosomes in cancer development and their potential applications in clinical settings. The authors discuss the role of exosomes in cancer progression, including their involvement in tumor growth, metastasis, and immune evasion. They also highlight the potential of exosomes as diagnostic biomarkers, therapeutic agents, and vaccine delivery vehicles. The review covers the current state of exosome-based therapies, including their advantages and limitations, and discusses the challenges and opportunities in translating exosome research into clinical practice. The authors conclude that exosomes have great potential for improving cancer diagnosis and treatment, but further research is needed to fully understand their mechanisms and optimize their therapeutic applications (Level 5).
Tai等[46]回顾了目前对外泌体在癌症发展中的理解及其在临床环境中的潜在应用。作者讨论了外泌体在癌症进展中的作用,包括它们参与肿瘤生长、转移和免疫逃逸。他们还强调了外泌体作为诊断生物标志物、治疗剂和疫苗递送载体的潜力。该综述涵盖了基于外泌体的疗法的现状,包括其优点和局限性,并讨论了将外泌体研究转化为临床实践的挑战和机遇。作者得出结论,外泌体在改善癌症诊断和治疗方面具有巨大潜力,但需要进一步研究以充分了解其机制并优化其治疗应用(5 级)。
Skuratovskaia et al. [47] review the current state of exosomes in the treatment of inflammatory diseases. The authors highlight the potential benefits of exosomes as a therapeutic platform, including their ability to deliver therapeutic molecules and modulate the immune response. However, they also discuss the limitations of exosome-based therapies, including issues with scalability, standardization, and stability. The review covers the challenges of exosome production, purification, and characterization, as well as the difficulties in delivering exosomes to target tissues and organs. The authors conclude that while exosomes show promise for treating inflammatory diseases, further research is needed to overcome these limitations and optimize their therapeutic potential (Level 4).
Skuratovskaia等[47]综述了外泌体治疗炎症性疾病的现状。作者强调了外泌体作为治疗平台的潜在好处,包括它们递送治疗分子和调节免疫反应的能力。然而,他们还讨论了基于外泌体的疗法的局限性,包括可扩展性、标准化和稳定性问题。该综述涵盖了外泌体生产、纯化和表征的挑战,以及将外泌体递送到靶组织和器官的困难。作者得出结论,虽然外泌体显示出治疗炎症性疾病的前景,但需要进一步的研究来克服这些限制并优化其治疗潜力(4 级)。
Lu et al. [48] investigate the potential of exosome-derived biomarkers for diagnosing and monitoring atherosclerosis. The authors analyzed exosomal RNA and protein cargo from the plasma samples of patients with atherosclerosis and healthy controls. They found that exosomal miR-126-3p and PD-L1 were significantly increased in patients with
Lu et al. [48] 研究了外泌体衍生的生物标志物在诊断和监测动脉粥样硬化方面的潜力。作者分析了动脉粥样硬化患者和健康对照者血浆样本中的外泌体 RNA 和蛋白质转运蛋白。他们发现,外泌体 miR-126-3p 和 PD-L1 在

atherosclerosis, while exosomal miR-145-5p was decreased. The authors used these biomarkers to develop a diagnostic model that showed high accuracy in distinguishing patients with atherosclerosis from healthy controls. The study also explored the clinical application of exosome-derived biomarkers in patients with coronary artery disease (Level 1b).
动脉粥样硬化,而外泌体 miR-145-5p 降低。作者使用这些生物标志物开发了一种诊断模型,该模型在区分动脉粥样硬化患者和健康对照者方面显示出很高的准确性。该研究还探讨了外泌体来源的生物标志物在冠状动脉疾病患者 (Level 1b) 中的临床应用。
Dimik et al. [49] provide a comprehensive review of the current therapeutic applications and potential capabilities of exosomes in human reproduction. The authors discuss the role of exosomes in fertility, pregnancy, and reproductive health, including their ability to deliver therapeutic molecules and modulate the immune response. They also highlight the potential uses of exosomes in assisted reproductive technologies, such as in vitro fertilization and embryo transfer. The review covers the current state of research on exosomes in human reproduction, including their mechanism of action, advantages, and challenges. The authors conclude that exosomes have great potential for improving human reproductive health and fertility outcomes (Level 2c).
Dimik等[49]全面综述了外泌体在人类生殖中的当前治疗应用和潜在能力。作者讨论了外泌体在生育、怀孕和生殖健康中的作用,包括它们递送治疗分子和调节免疫反应的能力。他们还强调了外泌体在辅助生殖技术中的潜在用途,例如体外受精和胚胎移植。该综述涵盖了人类生殖中外泌体的研究现状,包括它们的作用机制、优势和挑战。作者得出结论,外泌体在改善人类生殖健康和生育结果(2c 级)方面具有巨大潜力。
He et al. [50] provide an overview of the concept of exosome theranostics, which involves the use of exosomes as both therapeutic agents and diagnostic tools. The authors discuss the biology of exosomes, including their origin, composition, and function, as well as their potential applications in various diseases. They highlight the advantages of exosomes as a delivery platform, including their ability to target specific cells and tissues and their potential for reducing side effects. The authors also review the current state of exosome-based theranostics in cancer, cardiovascular disease, and neurological disorders. They conclude that exosome theranostics has great potential for improving disease diagnosis and treatment (Level 5).
他等[50]概述了外泌体治疗诊断学的概念,其中涉及使用外泌体作为治疗剂和诊断工具。作者讨论了外泌体的生物学特性,包括它们的来源、组成和功能,以及它们在各种疾病中的潜在应用。他们强调了外泌体作为递送平台的优势,包括它们靶向特定细胞和组织的能力以及它们减少副作用的潜力。作者还回顾了基于外泌体的治疗诊断学在癌症、心血管疾病和神经系统疾病中的现状。他们得出结论,外泌体治疗诊断学在改善疾病诊断和治疗方面具有巨大潜力(5 级)。
Dorayappan et al. [51] discuss the role of exosomes in ovarian cancer, focusing on their biological significance and potential clinical applications. The authors review the current literature on exosome biology, including their origin, composition, and function in ovarian cancer. They highlight the potential of exosomes as diagnostic and therapeutic tools, including their ability to deliver therapeutic molecules and modulate the immune response. The authors also discuss the potential uses of exosomes in ovarian cancer diagnosis, including their ability to detect specific biomarkers and monitor disease progression. They conclude that exosomes have great potential for improving our understanding of ovarian cancer and developing new treatments (Level 1b).
Dorayappan等[51]讨论了外泌体在卵巢癌中的作用,重点介绍了它们的生物学意义和潜在的临床应用。作者回顾了当前关于外泌体生物学的文献,包括它们在卵巢癌中的起源、组成和功能。他们强调了外泌体作为诊断和治疗工具的潜力,包括它们递送治疗分子和调节免疫反应的能力。作者还讨论了外泌体在卵巢癌诊断中的潜在用途,包括它们检测特定生物标志物和监测疾病进展的能力。他们得出的结论是,外泌体在提高我们对卵巢癌的理解和开发新疗法(1b 级)方面具有巨大潜力。
Lorenc et al. [52] provide an overview of the current perspectives on the clinical use of exosomes as a personalized contrast to media and theranostics. The authors discuss the potential applications of exosomes in various medical fields, including imaging, diagnosis, and therapy. They highlight the advantages of exosomes, such as their ability to target specific cells and tissues and their potential for personalized medicine. The authors also discuss the challenges and limitations of exosome research, including the need for the standardization of exosome production and purification methods. They conclude that exosomes have great potential for clinical use, but further research is needed to fully understand their properties and potential (Level 5).
Lorenc 等 [52] 概述了目前关于外泌体作为与培养基和治疗诊断学的个性化对比的临床应用的观点。作者讨论了外泌体在各个医学领域的潜在应用,包括成像、诊断和治疗。他们强调了外泌体的优势,例如它们靶向特定细胞和组织的能力以及它们个性化医疗的潜力。作者还讨论了外泌体研究的挑战和局限性,包括外泌体生产和纯化方法标准化的必要性。他们得出结论,外泌体具有巨大的临床应用潜力,但需要进一步研究以充分了解它们的特性和潜力(5 级)。
Codispoti et al. [53] introduces a novel approach to regenerative medicine using NANOmetric BIO-banked MSC-derived exosomes (NANOBIOME). The authors describe the development of a proprietary method for isolating and preserving exosomes derived from mesenchymal stem cells (MSCs). The NANOBIOME technology involves the use of nanotechnology to enhance the stability and potency of the exosomes, which are then banked for future use. The authors highlight the potential advantages of this approach, including the ability to standardize and scale up exosome production and the potential for use in a wide range of therapeutic applications. The authors also discuss the initial results of preclinical studies using NANOBIOME, which show promising results in terms of tissue repair and regeneration (Level 2c).
Codispoti等[53]介绍了一种使用纳米生物库MSC衍生外泌体(NANOBIOME)的再生医学新方法。作者描述了一种分离和保存间充质干细胞 (MSC) 来源的外泌体的专有方法的开发。NANOBIOME 技术涉及使用纳米技术来增强外泌体的稳定性和效力,然后将其储存起来以备将来使用。作者强调了这种方法的潜在优势,包括标准化和扩大外泌体生产的能力以及用于广泛治疗应用的潜力。作者还讨论了使用 NANOBIOME 进行临床前研究的初步结果,这些结果在组织修复和再生(2c 级)方面显示出有希望的结果。
Tang et al. [54] provide a comprehensive review of the clinical implications, applications, and challenges of cancer exosomes. The authors discuss the role of exosomes in cancer progression, metastasis, and immune evasion, and highlight their potential as diagnostic and therapeutic biomarkers. They also explore the challenges and limitations of
Tang等[54]对癌症外泌体的临床意义、应用和挑战进行了全面综述。作者讨论了外泌体在癌症进展、转移和免疫逃逸中的作用,并强调了它们作为诊断和治疗生物标志物的潜力。他们还探讨了

exosome-based research, including the need for standardization of exosome isolation and characterization methods. The authors also discuss the potential applications of exosomes in cancer therapy, including the use of exosomes as vectors for cancer gene therapy, and the development of exosome-based immunotherapy. The authors conclude that while there are many challenges to overcome, cancer exosomes have great potential for improving cancer diagnosis and treatment (Level 5).
基于外泌体的研究,包括外泌体分离和表征方法标准化的需求。作者还讨论了外泌体在癌症治疗中的潜在应用,包括使用外泌体作为癌症基因治疗的载体,以及基于外泌体的免疫疗法的开发。作者得出结论,虽然有许多挑战需要克服,但癌症外泌体在改善癌症诊断和治疗方面具有巨大潜力(5 级)。
Willis et al. [41] discuss the potential of exosomes as a therapeutic platform for cardiovascular diseases. The authors highlight the challenges in developing exosome-based therapies, including the need for standardized methods for isolating and characterizing exosomes. They discuss the heterogeneity of exosomes and the importance of understanding their biological functions and potency. The authors also explore the concept of “fit-forpurpose” potency, which refers to the ability of exosomes to achieve specific therapeutic goals. They conclude that further research is needed to develop exosome-based therapies that can effectively treat cardiovascular diseases (Level 2c).
Willis等[41]讨论了外泌体作为心血管疾病治疗平台的潜力。作者强调了开发基于外泌体的疗法所面临的挑战,包括需要采用标准化方法来分离和表征外泌体。他们讨论了外泌体的异质性以及了解其生物学功能和效力的重要性。作者还探讨了“适合用途”效力的概念,它指的是外泌体实现特定治疗目标的能力。他们得出的结论是,需要进一步的研究来开发可以有效治疗心血管疾病(2c 级)的基于外泌体的疗法。
Wang et al. [55] explore the potential of exosomes as a novel therapeutic approach for targeting cancer stem cells. The authors discuss the unique features of exosomes, including their ability to selectively target cancer cells and evade immune recognition. They review the current understanding of exosome-based cancer therapy, including the use of exosomes to deliver therapeutic agents, such as siRNAs and chemotherapeutics, to cancer cells. The authors highlight the potential benefits of exosome-based therapy, including improved targeting of cancer stem cells and reduced side effects compared to traditional chemotherapy. They also discuss the challenges and limitations associated with exosome-based therapies, including the need for standardization and scalability of exosome production (Level 5).
Wang等[55]探讨了外泌体作为靶向癌症干细胞的新型治疗方法的潜力。作者讨论了外泌体的独特特征,包括它们选择性靶向癌细胞和逃避免疫识别的能力。他们回顾了目前对基于外泌体的癌症治疗的理解,包括使用外泌体将治疗剂(如 siRNA 和化疗药物)递送到癌细胞。作者强调了基于外泌体的疗法的潜在好处,包括与传统化疗相比,提高对癌症干细胞的靶向性和减少副作用。他们还讨论了与基于外泌体的疗法相关的挑战和限制,包括外泌体生产的标准化和可扩展性的需求(5 级)。
Tzng et al. [56] highlight the current challenges and limitations surrounding the development of exosome-based treatments. The authors discuss the lack of standardization and scalability in exosome production, which hinders the translation of exosome-based therapies from bench to bedside. They also emphasize the need for improved characterization and tracking of exosomes, as well as the development of robust manufacturing processes to ensure consistency and quality. The authors also highlight the challenges associated with regulatory approval and reimbursement, as well as the need for further research on the safety and efficacy of exosome-based therapies. They conclude that addressing these challenges will be crucial for the successful development of exosome-based treatments (Level 2b).
Tzng等[56]强调了当前围绕基于外泌体的治疗方法开发的挑战和局限性。作者讨论了外泌体生产缺乏标准化和可扩展性,这阻碍了基于外泌体的疗法从实验室到床边的转化。他们还强调需要改进外泌体的表征和追踪,以及开发稳健的制造工艺以确保一致性和质量。作者还强调了与监管审批和报销相关的挑战,以及进一步研究基于外泌体的疗法的安全性和有效性的必要性。他们得出的结论是,应对这些挑战对于成功开发基于外泌体的治疗方法(2b 级)至关重要。
Nafar et al. [57] review the potential of exosomes as a target for cancer treatment. The authors discuss the role of exosomes in cancer development and progression, and highlight their potential as therapeutic agents for cancer treatment. They review the current state of knowledge on exosome-based therapies, including their use in targeted therapy, immunotherapy, and gene therapy. The authors also discuss the challenges associated with exosome-based therapies, including the need for improved understanding of exosome biology and the development of standardized manufacturing processes (Level 2b).
Nafar等[57]综述了外泌体作为癌症治疗靶点的潜力。作者讨论了外泌体在癌症发展和进展中的作用,并强调了它们作为癌症治疗剂的潜力。他们回顾了基于外泌体的疗法的知识现状,包括它们在靶向治疗、免疫疗法和基因疗法中的应用。作者还讨论了与基于外泌体的疗法相关的挑战,包括需要提高对外泌体生物学的理解和标准化制造工艺的开发(2b 级)。
Table 4 provides a summary of the exosomes in diagnostic and therapeutic tools.
表 4 提供了诊断和治疗工具中外泌体的摘要。
Table 4. Key points and classification of the of the exosomes in diagnostic and therapeutic tools.
表 4.诊断和治疗工具中外泌体的要点和分类。
Authors 作者 Focus 重点 Key Points 要点
 结论水平
Conclusion
Level
Conclusion Level| Conclusion | | :---: | | Level |
Huda et al. [42] Huda等[42]

外泌体在生物医学应用中的潜在用途。 癌细胞衍生的外泌体在临床中的应用。
Potential uses of exosomes in
biomedical applications.
Cancer cell-derived exosomes
in clinical applications.
Potential uses of exosomes in biomedical applications. Cancer cell-derived exosomes in clinical applications.| Potential uses of exosomes in | | :---: | | biomedical applications. | | Cancer cell-derived exosomes | | in clinical applications. |

诊断、靶向药物递送和基因治疗。 在癌症发展中的作用,免疫逃避,
Diagnostics, targeted drug
delivery, and gene therapy.
Role in cancer development,
immune evasion,
Diagnostics, targeted drug delivery, and gene therapy. Role in cancer development, immune evasion,| Diagnostics, targeted drug | | :---: | | delivery, and gene therapy. | | Role in cancer development, | | immune evasion, |
Challenges and limitations noted.
指出挑战和局限性。
And targeted delivery. 以及有针对性的投放。
Authors Focus Key Points "Conclusion Level" Huda et al. [42] "Potential uses of exosomes in biomedical applications. Cancer cell-derived exosomes in clinical applications." "Diagnostics, targeted drug delivery, and gene therapy. Role in cancer development, immune evasion," Challenges and limitations noted. And targeted delivery. | Authors | Focus | Key Points | Conclusion <br> Level | | :---: | :---: | :---: | :---: | | Huda et al. [42] | Potential uses of exosomes in <br> biomedical applications. <br> Cancer cell-derived exosomes <br> in clinical applications. | Diagnostics, targeted drug <br> delivery, and gene therapy. <br> Role in cancer development, <br> immune evasion, | Challenges and limitations noted. | | And targeted delivery. | | | |
Table 4. Cont. 表 4.续。
Authors 作者 Focus 重点 Key Points 要点 Conclusion 结论 Evidence Level 证据水平
Lorenc et al. [52] Lorenc 等 [52] Exosomes as personalized contrast media and theranostics.
外泌体作为个性化造影剂和治疗诊断学。
Applications in imaging, diagnosis, therapy, and personalized medicine.
在成像、诊断、治疗和个性化医疗中的应用。
Further research needed to understand properties and potential.
需要进一步的研究来了解特性和潜力。
5
Codispoti et al. [53] Codispoti等[53] NANOmetric BIO-banked MSC-derived exosomes (NANOBIOME).
NANOmetric BIO 库 MSC 衍生外泌体 (NANOBIOME)。
Proprietary method for isolating and preserving exosomes; preclinical studies show promise.
分离和保存外泌体的专有方法;临床前研究显示出前景。
Potential for wide range of therapeutic applications.
具有广泛的治疗应用潜力。
2c
Tang et al. [54] Cancer exosomes: clinical implications and challenges.
癌症外泌体:临床意义和挑战。
Role in progression, metastasis, immune evasion, and therapy vectors.
在进展、转移、免疫逃逸和治疗媒介中的作用。
Challenges in standardization and characterization methods.
标准化和表征方法的挑战。
5
Tzng et al. [56] Tzng等[56]

基于外泌体的治疗的挑战。
Challenges
in exosome-based treatments.
Challenges in exosome-based treatments.| Challenges | | :--- | | in exosome-based treatments. |
Lack of standardization, scalability, and regulatory approval issues.
缺乏标准化、可扩展性和监管审批问题。
Need for improved characterization, tracking, and manufacturing processes.
需要改进表征、跟踪和制造流程。
2b
Nafar et al. [57] Nafar等[57] Exosomes in cancer treatment.
癌症治疗中的外泌体。
Role in development, progression, and therapeutic agents.
在发育、进展和治疗剂中的作用。
Challenges in understanding.
理解中的挑战。
5
Authors Focus Key Points Conclusion Evidence Level Lorenc et al. [52] Exosomes as personalized contrast media and theranostics. Applications in imaging, diagnosis, therapy, and personalized medicine. Further research needed to understand properties and potential. 5 Codispoti et al. [53] NANOmetric BIO-banked MSC-derived exosomes (NANOBIOME). Proprietary method for isolating and preserving exosomes; preclinical studies show promise. Potential for wide range of therapeutic applications. 2c Tang et al. [54] Cancer exosomes: clinical implications and challenges. Role in progression, metastasis, immune evasion, and therapy vectors. Challenges in standardization and characterization methods. 5 Tzng et al. [56] "Challenges in exosome-based treatments." Lack of standardization, scalability, and regulatory approval issues. Need for improved characterization, tracking, and manufacturing processes. 2b Nafar et al. [57] Exosomes in cancer treatment. Role in development, progression, and therapeutic agents. Challenges in understanding. 5| Authors | Focus | Key Points | Conclusion | Evidence Level | | :---: | :---: | :---: | :---: | :---: | | Lorenc et al. [52] | Exosomes as personalized contrast media and theranostics. | Applications in imaging, diagnosis, therapy, and personalized medicine. | Further research needed to understand properties and potential. | 5 | | Codispoti et al. [53] | NANOmetric BIO-banked MSC-derived exosomes (NANOBIOME). | Proprietary method for isolating and preserving exosomes; preclinical studies show promise. | Potential for wide range of therapeutic applications. | 2c | | Tang et al. [54] | Cancer exosomes: clinical implications and challenges. | Role in progression, metastasis, immune evasion, and therapy vectors. | Challenges in standardization and characterization methods. | 5 | | Tzng et al. [56] | Challenges <br> in exosome-based treatments. | Lack of standardization, scalability, and regulatory approval issues. | Need for improved characterization, tracking, and manufacturing processes. | 2b | | Nafar et al. [57] | Exosomes in cancer treatment. | Role in development, progression, and therapeutic agents. | Challenges in understanding. | 5 |

6. Recent Derivatives from Humans and Plants
6. 来自人类和植物的最新衍生物

Exosomes serve as vital messengers within the dermis, significantly influencing the behavior of fibroblasts, the cells primarily responsible for producing collagen and elastin. These proteins are essential for maintaining skin elasticity and strength. Exosomes facilitate communication between skin cells and fibroblasts, enhancing collagen and elastin synthesis, and increasing dermal fat, thereby promoting the skin’s regenerative and restorative capacities for anti-aging. This leads to improved skin texture and a reduction in wrinkles and fine lines. Additionally, exosomes contribute to elastin production, which is crucial for maintaining a youthful and firm skin appearance [58].
外泌体在真皮中充当重要的信使,显着影响成纤维细胞的行为,成纤维细胞主要负责产生胶原蛋白和弹性蛋白。这些蛋白质对于维持皮肤弹性和强度至关重要。外泌体促进皮肤细胞和成纤维细胞之间的通讯,增强胶原蛋白和弹性蛋白的合成,增加真皮脂肪,从而促进皮肤的再生和修复能力,以抗衰老。这可以改善皮肤质地并减少皱纹和细纹。此外,外泌体有助于弹性蛋白的产生,这对于保持年轻和紧致的皮肤外观至关重要[58]。
At the molecular level, exosomes exert their rejuvenating effects through various pathways and growth factors, notably TGF-B. TGF-B plays a critical role in skin repair and rejuvenation by influencing cell growth, proliferation, and differentiation. Exosomes carry and deliver TGF-B to target cells in the skin, triggering specific signaling cascades that improve skin structure and function.
在分子水平上,外泌体通过各种途径和生长因子(尤其是 TGF-B)发挥其恢复活力的作用。TGF-B 通过影响细胞生长、增殖和分化,在皮肤修复和年轻化中发挥关键作用。外泌体携带 TGF-B 并将其递送到皮肤中的靶细胞,触发改善皮肤结构和功能的特异性信号级联反应。
Furthermore, exosomes are involved in the modulation of the extracellular matrix (ECM), a complex network of proteins and other molecules that provide structural and biochemical support to surrounding cells. They assist in remodeling this matrix, which is particularly important in wound healing and the prevention of scar formation.
此外,外泌体参与细胞外基质 (ECM) 的调节,ECM 是蛋白质和其他分子的复杂网络,为周围细胞提供结构和生化支持。它们有助于重塑这种基质,这在伤口愈合和预防疤痕形成方面尤为重要。
Recently, there has been a growing focus on exosomes derived from the human pharynx (EXOP, Sihler Inc., Seoul, Republic of Korea and Exodew, Hyundaimeditech Inc., Seoul, Republic of Korea) (Figure 4). Stem cells collected through swab-based sampling during examinations, such as influenza screenings in early childhood, are known for their exceptional differentiation capabilities (Figure 5) [59].
最近,人们越来越关注源自人咽部的外泌体(EXOP,Sihler Inc.,韩国首尔和 Exodew,Hyundaimeditech Inc.,韩国首尔)(图 4)。在检查过程中通过拭子采样收集的干细胞,例如儿童早期的流感筛查,以其卓越的分化能力而闻名(图 5)[59]。

Figure 4. There has been a recent surge in interest in exosomes derived from the human pharynx (EXOP by Sihler Inc., Seoul, Republic of Korea, and Exodew by Hyundai Meditech Inc., Wonju, Republic of Korea). Stem cells collected via swab-based sampling during pharyngeal examinations, such as those conducted for early childhood influenza, are recognized for their outstanding differentiation abilities.
图 4.最近,人们对源自人咽部的外泌体的兴趣激增(Sihler Inc. 的 EXOP 和韩国元州现代医疗技术公司的 Exodew)。在咽部检查(例如针对儿童早期流感的检查)中通过拭子取样采集的干细胞因其出色的分化能力而受到认可。

Figure 5. Pharyngeal stem cells obtained through swab-based sampling during examinations, such as influenza screenings in early childhood, are recognized for their remarkable differentiation capabilities.
图 5.在检查期间通过拭子取样获得的咽干细胞,例如儿童早期的流感筛查,因其显著的分化能力而得到认可。
In the realm of plant-based research, ginseng-derived exosomes have been actively explored, leveraging the long-established benefits of ginseng in Asian countries, where it has been extensively studied and used in cosmetics. This has led to the emergence of companies dedicated to studying exosomes extracted from ginseng (Exodew, Hyundaimeditech Co., Wonjusi, Republic of Korea) being a notable product. Ginseng, renowned for its antiinflammatory, anti-cancer, immunostimulant, and osteogenic/anti-osteoporotic properties, has recently been utilized to derive exosomes.
在植物性研究领域,人们积极探索人参衍生的外泌体,利用人参在亚洲国家长期存在的好处,在那里人参得到了广泛的研究和用于化妆品。这导致出现了致力于研究从人参中提取的外泌体的公司(Exodew,Hyundaimeditech Co.,Wonjusi,大韩民国)是一个著名的产品。人参以其抗炎、抗癌、免疫刺激剂和成骨/抗骨质疏松特性而闻名,最近被用于衍生外泌体。
A study by Seo et al. [60] confirmed that these exosomes inhibit osteoclast differentiation, and investigated the underlying molecular mechanisms.
Seo等[60]的一项研究证实,这些外泌体抑制破骨细胞分化,并研究了潜在的分子机制。
Exosomes were isolated using centrifugation with a sucrose gradient, and their properties were analyzed through dynamic light scattering, zeta potential measurements, and transmission electron microscopy. Bone marrow-derived macrophages (BMMs) were used to assess the cytotoxicity of exosomes and their ability to inhibit osteoclast differentiation. The results demonstrated that exosomes maintained high BMM viability and proliferation while inhibiting osteoclastogenesis. At concentrations greater than 1 μ g / mL 1 μ g / mL 1mug//mL1 \mu \mathrm{~g} / \mathrm{mL}, the exosomes
使用蔗糖梯度离心分离外泌体,并通过动态光散射、zeta 电位测量和透射电子显微镜分析其特性。骨髓来源的巨噬细胞 (BMMs) 用于评估外泌体的细胞毒性及其抑制破骨细胞分化的能力。结果表明,外泌体在抑制破骨细胞生成的同时保持了较高的 BMM 活力和增殖。在浓度大于 1 μ g / mL 1 μ g / mL 1mug//mL1 \mu \mathrm{~g} / \mathrm{mL} 时,外泌体

significantly impeded osteoclast differentiation, as confirmed by tartrate-resistant acid phosphatase and F-actin staining.
显着阻碍破骨细胞分化,酒石酸盐抗性酸性磷酸酶和 F-肌动蛋白染色证实。
Exosomes also suppressed the RANKL-induced signaling pathways, including I I B α I B α IBalpha\mathrm{I} \mathrm{B} \alpha, c-JUN N-terminal kinase, and extracellular signal-regulated kinase, as well as the genes regulating osteoclast maturation. The exosomes were rich in Rb 1 and Rg 1 ginsenosides, and were more effective at inhibiting osteoclast differentiation than these ginsenosides alone or in combination.
外泌体还抑制 RANKL 诱导的信号通路,包括 I I B α I B α IBalpha\mathrm{I} \mathrm{B} \alpha 、 c-JUN N 末端激酶和细胞外信号调节激酶,以及调节破骨细胞成熟的基因。外泌体富含 Rb 1 和 Rg 1 人参皂苷,在抑制破骨细胞分化方面比单独或组合这些人参皂甙更有效。
Additionally, the unique properties of exosomes can be applied in esthetics. Their antiinflammatory and immunostimulant effects could be beneficial for skin health, potentially aiding in the treatment of inflammatory skin conditions and enhancing skin rejuvenation. The osteogenic properties might also support facial bone health, contributing to a more youthful appearance.
此外,外泌体的独特特性可以应用于美学。它们的抗炎和免疫刺激作用可能对皮肤健康有益,可能有助于治疗炎症性皮肤病和增强皮肤年轻化。成骨特性也可能支持面部骨骼健康,有助于更年轻的外观。
Another study by Jang et al. [61] highlighted that exosomes are nano-sized extracellular vesicles that play a crucial role in regulating cell growth and defense by delivering bioactive cellular components. They hold significant promise for biomedical and cosmetic applications, particularly from medicinal crops like ginseng. However, isolating stable exosomes with high purity remains a major challenge.
Jang等[61]的另一项研究强调,外泌体是纳米级的细胞外囊泡,通过传递生物活性细胞成分,在调节细胞生长和防御方面起着至关重要的作用。它们在生物医学和化妆品应用方面具有重要前景,尤其是人参等药用作物。然而,分离高纯度的稳定外泌体仍然是一项重大挑战。
This study tested three methods to isolate exosomes from ginseng: ultracentrifugation (the most widely used method), the ExoQuick system (a polymer-based exosome precipitation approach), and a combination of both methods. Size distribution analysis showed that the purity of exosome isolation was 34.1 % 34.1 % 34.1%34.1 \% with ultracentrifugation, 59.7 % 59.7 % 59.7%59.7 \% with ExoQuick, and significantly improved to 83.3 % 83.3 % 83.3%83.3 \% with the combination method.
本研究测试了三种从人参中分离外泌体的方法:超速离心(使用最广泛的方法)、ExoQuick 系统(一种基于聚合物的外泌体沉淀方法)以及两种方法的组合。大小分布分析表明, 59.7 % 59.7 % 59.7%59.7 \% 使用超速离心和 ExoQuick 分离外泌体的纯度,并且与联合方法相比 83.3 % 83.3 % 83.3%83.3 \% ,外泌体分离 34.1 % 34.1 % 34.1%34.1 \% 的纯度显著提高。
The combination method not only enhanced exosome isolation purity, but also increased the colloidal stability of the isolated ginseng exosomes, almost doubling the stability achieved by ultracentrifugation alone. Additionally, this method was effective in isolating high-purity and high-stability exosomes from the model plant Arabidopsis.
该组合方法不仅提高了外泌体分离的纯度,而且增加了分离的人参外泌体的胶体稳定性,几乎是单独超速离心所达到的稳定性的两倍。此外,该方法可有效从模式植物拟南芥中分离高纯度和高稳定性的外泌体。
Overall, these findings indicate that the combination method is highly suitable for isolating high-purity and high-stability exosomes from plants, including ginseng, making it a promising approach for both biomedical and cosmetic uses.
总体而言,这些发现表明该组合方法非常适合从植物(包括人参)中分离高纯度和高稳定性的外泌体,使其成为生物医学和化妆品用途的一种有前途的方法。

7. Emphasizing the Importance of the Donor Source for Exosomes
7. 强调外泌体供体来源的重要性

When producing exosomes for therapeutic purposes, variations depending on the donor must be considered because various donors can produce exosomes with diverse forms of functional characteristics. The recent literature underscores the critical importance of the exosome source in determining quality, safety, and potency, with donor age particularly influencing regulatory capacity, proliferative potential, and differentiation capacity. Furthermore, a vigilant review on the harvesting and selection procedures of donor cells, donor suitability criteria, health status, and medical history shall be made. ZISHEL BIO, a leading exosomal biotech company based in South Korea, has set a pioneering standard to seamlessly integrate an in-house standard for screening and harvesting donor cells in partnership with is in-house certified lab clinic. Stressing the importance of donor source cells, the company leads comprehensive donor profiling, virus checking, and harvesting services, following rigorous, standardized methods. General steps from screening, keeping health data, and inspections are as follows (Figure 6).
当生产用于治疗目的的外泌体时,必须考虑取决于供体的变化,因为不同的供体可以产生具有不同形式功能特征的外泌体。最近的文献强调了外泌体来源在决定质量、安全性和效力方面的重要性,供体年龄尤其影响调节能力、增殖潜力和分化能力。此外,应仔细审查供体细胞的收获和选择程序、供体适合性标准、健康状况和病史。ZISHEL BIO 是一家总部位于韩国的领先外泌体生物技术公司,它制定了一项开创性标准,与内部认证的实验室诊所合作,无缝集成用于筛选和收获供体细胞的内部标准。该公司强调供体来源细胞的重要性,遵循严格的标准化方法,领导全面的供体分析、病毒检查和收获服务。筛查、保存健康数据和检查的一般步骤如下(图 6)。

Figure 6. Recent technology using screening to keep the health data of donors and inspections of exosomes.
图 6.最近的技术使用筛选来保存供体的健康数据和外泌体的检查。

It is essential to screen for signs of infection before collecting tissue and cells from a donor. The ‘Cell Therapy Donor Suitability Evaluation Guidelines’ apply to the suitability criteria for donors who provide cells or tissues for exosome production.
在从供体那里收集组织和细胞之前,必须筛查感染迹象。“细胞治疗供体适用性评估指南”适用于为外泌体生产提供细胞或组织的供体的适用性标准。

(1) Procedure for Doner’s Screening and Testing for Stem Cell Therapy
(1) 干细胞治疗的 Doner's 筛查和检测程序
  • Doner conducts the below procedures in accordance with the international guidelines and national regulations.
    Doner 根据国际准则和国家法规执行以下程序。

    (*) Donor Test Standard Parameters
    (*)供体检测标准参数

    According to the Human Cell Tissue Culture Safety Standards, donors are checked for the following infectious diseases:
    根据人类细胞组织培养安全标准,检查供体是否存在以下传染病:

    (1) Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), Human T-lymphotropic virus (HTLV), ParvovirusB19, Cytomegalovirus (CMV), and Epstein-Barr virus (EBV) Infectious Diseases.
    (1) 乙型肝炎病毒 (HBV)、丙型肝炎病毒 (HCV)、人类免疫缺陷病毒 (HIV)、人类嗜 T 淋巴细胞病毒 (HTLV)、细小病毒 B19、巨细胞病毒 (CMV) 和爱泼斯坦-巴尔病毒 (EBV) 传染病。

    (2) Transmissible spongiform encephalopathy and suspicion on transmissible spongiform encephalopathy.
    (2) 传染性海绵状脑病和怀疑传染性海绵状脑病。

    (3) Infections caused by bacteria such as chlamydia, gonorrhea, and tuberculosis Syphilis Treponema.
    (3) 衣原体、淋病和结核病梅毒密螺旋体等细菌引起的感染。

    (4) Sepsis and suspected sepsis.
    (4) 败血症和疑似败血症。

    (5) Congenital or chronic diseases that can affect cellular structure.
    (5) 可影响细胞结构的先天性或慢性疾病。

    (2) Open-Source QR Data of the Donor Cells
    (2) 供体细胞的开源 QR 数据
Doner’s basic information, suitability test, disease history, etc., can be provided using a QR code. By providing this information about the donor, we provide trust and stability to patients receiving exosome treatment.
Doner 的基本信息、适宜性测试、病史等,都可以使用二维码提供。通过提供有关捐赠者的这些信息,我们为接受外泌体治疗的患者提供信任和稳定性。

** QR Data of the Doner: Gender, Age, Harvested cell type, Date/Site of Collection, Donor Eligibility Assessment Results
** 捐赠者的二维码数据:性别、年龄、收获的细胞类型、采集日期/地点、捐赠者资格评估结果
Again, exosomes have emerged as a therapeutic option for regenerative medicine and promoting overall health. As their potential as therapeutics is attracting attention, many exosome biotech companies are making efforts to develop and produce therapeutic exosomes. To develop and commercialize the exosome therapeutics, they must develop a new production scheme with the added standardization and validation of exosomes. Scalability, purity, and stability considerations shall be taken into account from the initial source cell harvesting step to the production and isolation step. Such considerations in terms of production and quality are detailed as follows.
外泌体再次成为再生医学和促进整体健康的治疗选择。随着它们作为治疗剂的潜力受到关注,许多外泌体生物技术公司正在努力开发和生产治疗性外泌体。为了开发和商业化外泌体疗法,他们必须开发一种新的生产方案,并增加外泌体的标准化和验证。从初始源细胞收获步骤到生产和分离步骤,都应考虑可扩展性、纯度和稳定性。生产和质量方面的此类考虑详细说明如下。

(1) Overall Production (1) 整体生产

Since source cells from the donor are used to produce potent and high-purity-based exosomes, the characteristics profile of stem cells used as a starting source must be analyzed and recorded. In addition to the donor source suitability evaluation, the following analyses of the stem cells are made to ensure identification and genetic stability of the source cells. In addition, standardized methods to evaluate the potency and reproducibility of the exosomes based on various criteria are followed to ensure consistent exosome production with added quality and consistency.
由于来自供体的源细胞用于产生有效和高纯度的外泌体,因此必须分析和记录用作起始来源的干细胞的特性概况。除了供体来源适用性评估外,还对干细胞进行了以下分析,以确保来源细胞的鉴定和遗传稳定性。此外,遵循基于各种标准评估外泌体效力和可重复性的标准化方法,以确保外泌体生产一致,并提高质量和一致性。
  • Identification of cells (chromosomal karyotype analysis, cell surface phenotypic markers, specific gene expression levels, etc.).
    细胞鉴定(染色体核型分析、细胞表面表型标志物、特异性基因表达水平等)。
  • Stability (shape, growth characteristics, etc.), genetic stability (karyotype analysis, etc.), microbial test (virus, bacteria, fungus, mycoplasma, etc.).
    稳定性(形状、生长特性等)、遗传稳定性(核型分析等)、微生物检测(病毒、细菌、真菌、支原体等)。
  • Proof of standardization and reproducibility of the exosome production process (density, survival rate, cell properties, subculture method, culturing time carbon dioxide concentration, culture temperature, medium additives, medium composition, culture vessel, etc.)
    外泌体生产过程的标准化和可重复性证明(密度、存活率、细胞特性、传代培养方法、培养时间、二氧化碳浓度、培养温度、培养基添加剂、培养基成分、培养容器等)
  • Standardization for isolating and purifying exosome (TFF-exosome isolation).
    分离和纯化外泌体的标准化(TFF-外泌体分离)。
Every step, from sourcing to the isolation of exosomes, must adhere to the highest production standards to guarantee optimal efficacy. As highlighted by Théry et al. [62], factors such as processing and storage significantly impact exosome physiology and, consequently, influence exosome research. ZISHEL BIO’s distinctive all-in-one production pipeline prioritize efficiency and purity. Notably, the harvesting-to-culturing gap time is minimized to less than 5 min . Such practice allows our team to avoid long time delivery/storage and freezing and thawing process of the harvested media, minimizing every possible risk of disturbing the cells. This streamlined approach results in a substantial increase in both cell and exosome potency and viability. Importantly, this rapid processing occurs without introducing any mutations or stress factors that could compromise the safety and efficacy of the final product.
从外泌体的采购到分离,每一步都必须遵守最高的生产标准,以保证最佳疗效。正如Théry等[62]所强调的那样,加工和储存等因素会显著影响外泌体生理学,从而影响外泌体研究。ZISHEL BIO 独特的一体化生产管道优先考虑效率和纯度。值得注意的是,收获到培养的间隔时间最短至 5 分钟以下。这种做法使我们的团队能够避免长时间交付/储存以及收获培养基的冷冻和解冻过程,从而最大限度地减少干扰细胞的所有可能风险。这种简化的方法导致细胞和外泌体的效力和活力显着增加。重要的是,这种快速加工不会引入任何可能影响最终产品安全性和有效性的突变或应激因素。

(2) Quality Considerations for the Optimization of Produced Exosomes
(2) 优化所产生外泌体的质量考虑

After producing exosomes, standardized guidelines for quality control shall be formulated in every possible process.
生产外泌体后,应在每个可能的过程中制定标准化的质量控制指南。
  • Various characteristics of exosomes produced through the separation process must be analyzed (analyzing the profiles of exosome nano particles, size, protein, mRNA, and lipid).
    必须分析通过分离过程产生的外泌体的各种特性(分析外泌体纳米颗粒、大小、蛋白质、mRNA 和脂质的概况)。
  • Qualitative/quantitative testing methods and acceptable limits for impurities must be established.
    必须确定定性/定量检测方法和可接受的杂质限值。
  • Mycoplasma, viruses, bacteria, fungi, endotoxin.
    支原体、病毒、细菌、真菌、内毒素。
  • The quality and stability of extracellular vesicle treatments are tested according to the ‘Stability Test Standards for Pharmaceuticals’, etc. (FDA guide).
    细胞外囊泡治疗的质量和稳定性根据“药物稳定性测试标准”等(FDA 指南)进行测试。

    Although there are still many challenges and uncertainties that need to be addressed, the recent development of standardized methods for isolating and purifying exosomes is led by ZISHEL BIO, a leading biotech company for exosomes R&D based in South Korea. Powered by ZISHEL BIO’s puriMAX Technology, a customized solution for maximizing purity and standardized exosomes, purimaxomes are controlled in-house through validations from screening of harvested cells to culturing and isolation. The MSC-derived cultivated cells are screened and quality controlled via its proprietary process known as ctrlSource codes. The health data and inspections are recorded and made traceable. Purimaxomes’ culture and isolation processes are developed and classified under high- and low-end production technologies. To increase the overall production capability and consistency of exosome production, puriMax Technology is built as the innovative double-looped scheme to tackle some of the unmet challenges.
    尽管仍有许多挑战和不确定性需要解决,但最近开发的分离和纯化外泌体的标准化方法是由 ZISHEL BIO 领导的,ZISHEL BIO 是一家位于韩国的领先外泌体研发生物技术公司。由 ZISHEL BIO 的 puriMAX 技术提供支持,该技术是一种用于最大限度地提高纯度和标准化外泌体的定制解决方案,purimaxomes 通过从收获细胞筛选到培养和分离的验证在内部进行控制。MSC 衍生的培养细胞通过其专有流程 ctrlSource codes 进行筛选和质量控制。健康数据和检查被记录下来并使其可追溯。Purimaxomes 的培养和分离工艺根据高端和低端生产技术进行开发和分类。为了提高外泌体生产的整体生产能力和一致性,puriMax 技术被构建为创新的双环方案,以应对一些未解决的挑战。

8. Future Insights and Potential Plans
8. 未来的见解和潜在的计划

This review of the literature highlights the vast potential of exosomes as therapeutic agents in various diseases, including cancer, cardiovascular disease, neurological disorders, and autoimmune disorders. The benefits of exosomes as therapeutic agents are numerous, including their ability to deliver therapeutic cargo, modulate immune responses, and promote tissue repair. The results of preclinical studies and clinical trials demonstrate the efficacy and safety of exosome-based therapies, which have shown promise in treating various diseases.
这篇文献综述强调了外泌体作为各种疾病治疗剂的巨大潜力,包括癌症、心血管疾病、神经系统疾病和自身免疫性疾病。外泌体作为治疗剂的好处很多,包括它们能够递送治疗货物、调节免疫反应和促进组织修复。临床前研究和临床试验的结果表明,基于外泌体的疗法的有效性和安全性,这些疗法在治疗各种疾病方面显示出前景。
However, there are also several limitations and challenges associated with exosomebased therapies. One of the main challenges is the standardization and validation of exosome-based products, including issues with scalability, purity, and stability. Additionally, the regulatory framework for exosome-based therapies is still evolving, and there is a need for further research to understand the biological mechanisms underlying exosomemediated delivery [20].
然而,基于外泌体的疗法也存在一些局限性和挑战。主要挑战之一是基于外泌体的产品的标准化和验证,包括可扩展性、纯度和稳定性问题。此外,基于外泌体的疗法的监管框架仍在不断发展,需要进一步研究以了解外泌体介导递送的生物学机制 [20]。
Despite these challenges, there are several promising areas of research that hold great potential for the development of exosome-based therapies. For example, the use of mesenchymal stem cell-derived exosomes shows promise in treating various diseases, including cardiovascular disease, neurological disorders, and autoimmune disorders. The development of exosome-based vaccines is another area of research that has shown promising results in preclinical studies [14].
尽管存在这些挑战,但仍有几个有前途的研究领域在开发基于外泌体的疗法方面具有巨大潜力。例如,间充质干细胞衍生的外泌体的使用在治疗各种疾病方面显示出前景,包括心血管疾病、神经系统疾病和自身免疫性疾病。基于外泌体的疫苗的开发是另一个在临床前研究中显示出有希望的结果的研究领域 [14]。
In addition to these areas of research, there are several other potential applications of exosomes that warrant further investigation. For example, the use of exosomes in orthopedics could potentially treat conditions such as osteoarthritis, osteoporosis, and tendon injuries [ 35 , 36 ] [ 35 , 36 ] [35,36][35,36]. The use of exosomes in lung-regenerative medicine could potentially treat diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer [36,44,54].
除了这些研究领域之外,外泌体还有其他几个潜在的应用值得进一步研究。例如,在骨科中使用外泌体可能会治疗骨关节炎、骨质疏松症和肌腱损伤等疾病 [ 35 , 36 ] [ 35 , 36 ] [35,36][35,36] 。外泌体在肺再生医学中的应用可能治疗慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)、肺纤维化和肺癌等疾病[36,44,54]。
Despite the promising results of exosome-based therapies in various diseases, there are several challenges and limitations that need to be addressed. One of the main challenges is the standardization and validation of exosome-based products, including issues with scalability, purity, and stability. Additionally, the regulatory framework for exosomebased therapies is still evolving, and there is a need for further research to understand the biological mechanisms underlying exosome-mediated delivery.
尽管基于外泌体的疗法在各种疾病中取得了可喜的结果,但仍存在一些需要解决的挑战和限制。主要挑战之一是基于外泌体的产品的标准化和验证,包括可扩展性、纯度和稳定性问题。此外,基于外泌体的疗法的监管框架仍在不断发展,需要进一步研究以了解外泌体介导的递送的生物学机制。
Another challenge is the difficulty in tracking the fate of exosomes after administration. Exosomes are small particles that can be taken up by various cells and tissues, making it difficult to track their fate and determine their efficacy. Additionally, the development of methods for tracking the fate of exosomes is essential for understanding their mechanisms of action and optimizing their therapeutic potential.
另一个挑战是难以追踪外泌体给药后的命运。外泌体是可被各种细胞和组织吸收的小颗粒,因此难以追踪它们的命运并确定其功效。此外,开发追踪外泌体命运的方法对于了解其作用机制和优化其治疗潜力至关重要。
Several areas of research would be beneficial in advancing our understanding of exosome-based therapies and their potential applications, such as the following:
几个研究领域将有助于促进我们对基于外泌体的疗法及其潜在应用的理解,例如:
  • Further research is needed to develop methods for standardizing and validating exosome-based products.
    需要进一步的研究来开发标准化和验证基于外泌体的产品的方法。
  • The regulatory framework for exosome-based therapies needs to be further developed and clarified.
    基于外泌体的疗法的监管框架需要进一步发展和阐明。
  • The biological mechanisms underlying exosome-mediated delivery need to be fully understood.
    需要充分了解外泌体介导递送的生物学机制。
  • The development of methods for tracking the fate of exosomes needs to be advanced.
    追踪外泌体命运的方法的开发需要提前。
  • The use of exosomes in combination with other therapeutic agents needs to be explored.
    需要探索外泌体与其他治疗剂联合使用。
  • The development of personalized therapies using patient-derived exosomes needs to be investigated.
    需要研究使用患者来源的外泌体开发个性化疗法。

    In addition to these areas of research, there are several other potential applications of exosomes that warrant further investigation, as follows:
    除了这些研究领域外,外泌体还有其他几个潜在的应用值得进一步研究,如下所示:
  • The use of exosomes in regenerative medicine could potentially treat a range of conditions, including osteoarthritis, osteoporosis, and tendon injuries.
    在再生医学中使用外泌体可能会治疗一系列疾病,包括骨关节炎、骨质疏松症和肌腱损伤。
  • The use of exosomes in gene therapy could potentially treat a range of genetic disorders.
    在基因治疗中使用外泌体可能会治疗一系列遗传疾病。
  • The use of exosomes in vaccine development could potentially treat a range of diseases, including infectious diseases and cancer.
    在疫苗开发中使用外泌体可能会治疗一系列疾病,包括传染病和癌症。
  • The use of exosomes in diagnostic medicine could potentially be used as a diagnostic tool for a range of diseases.
    外泌体在诊断医学中的使用可能用作一系列疾病的诊断工具。

9. Conclusions 9. 结论

The clinical applications of exosomes is a rapidly evolving field with significant potential to revolutionize the treatment of various diseases. The data presented in this review highlight the versatility and efficacy of exosomes as a therapeutic agent, with promising results in the treatment of cardiovascular disease, cancer, and neurological disorders. The ability of exosomes to deliver targeted therapeutics, evade immune recognition, and promote tissue repair and regeneration make them an attractive option for clinicians.
外泌体的临床应用是一个快速发展的领域,具有彻底改变各种疾病治疗的巨大潜力。本综述中提供的数据强调了外泌体作为治疗剂的多功能性和有效性,在治疗心血管疾病、癌症和神经系统疾病方面取得了可喜的结果。外泌体提供靶向治疗、逃避免疫识别以及促进组织修复和再生的能力使其成为临床医生的有吸引力的选择。
However, despite the significant progress that has been made, there are still many challenges and uncertainties that need to be addressed. The development of standardized methods for isolating and purifying exosomes, as well as the optimization of exosomal cargo loading and stability, are critical areas of research that require further attention. Furthermore, the regulatory environment surrounding the use of exosomes as a therapeutic agent is still evolving, and guidelines for their clinical use are needed.
然而,尽管已经取得了重大进展,但仍有许多挑战和不确定性需要解决。分离和纯化外泌体的标准化方法的开发,以及外泌体货物负载和稳定性的优化,是需要进一步关注的关键研究领域。此外,围绕使用外泌体作为治疗剂的监管环境仍在不断发展,需要其临床使用指南。
Future research directions should focus on addressing these challenges and uncertainties. The development of biomarkers for exosomal cargo and the optimization of exosomal delivery methods are critical areas of research that have the potential to significantly improve the efficacy and safety of exosome-based therapies. Additionally, the exploration of exosomes as a diagnostic tool for various diseases is an area that warrants further investigation.
未来的研究方向应侧重于应对这些挑战和不确定性。外泌体货物生物标志物的开发和外泌体递送方法的优化是关键的研究领域,有可能显著提高基于外泌体的疗法的有效性和安全性。此外,探索外泌体作为各种疾病的诊断工具是一个值得进一步研究的领域。
Author Contributions: Conceptualization, K.W.A.L. and L.K.W.C.; Writing-Original Draft Preparation, K.W.A.L., L.K.W.C. and Y.P. Writing-Review and Editing, K.W.A.L., L.K.W.C., L.C.H. and L.K.W.P.; Visualization, K.W.A.L., L.K.W.C., Y.P. and K.-H.Y.; Supervision, K.-H.Y. All authors have read and agreed to the published version of the manuscript.
作者贡献:概念化、K.W.A.L. 和 L.K.W.C.;写作-初稿准备,K.W.A.L.、L.K.W.C. 和 Y.P. 写作-审查和编辑,K.W.A.L.、L.K.W.C.、L.C.H. 和 L.K.W.P.;可视化、K.W.A.L.、L.K.W.C.、Y.P. 和 K.-H.Y.;监督,K.-H.Y.所有作者均已阅读并同意手稿的已发表版本。
Funding: This research received no external funding.
资金: 这项研究没有获得外部资金。

Conflicts of Interest: I acknowledge that I have considered the conflicts of interest statement included in the “Author Guidelines.” I hereby certify that, to the best of my knowledge, that no aspect of my current personal or professional situation might reasonably be expected to significantly affect my views on the subject I am presenting.
利益冲突:我承认我已考虑“作者指南”中包含的利益冲突声明。我特此证明,据我所知,我目前的个人或职业状况的任何方面都不会合理地影响我对我所提出的主题的看法。

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