工程化外泌体研究现状与临床转化的挑战  

Recent advances of engineered exosomes and challenges on clinical translational research

作　　者：张琪 于湄[1] 刘磊[1] 田卫东[1] Zhang Qi;Yu Mei;Liu Lei;Tian Weidong(National Engineering Laboratory for Oral Regenerative Medicine,West China School of Stomatology,Sichuan University,Chengdu 610041,Sichuan Province,China)

机构地区：[1]四川大学华西口腔医(学)院,口腔再生医学国家地方联合工程实验室,四川省成都市610041

出　　处：《中国组织工程研究》2023年第19期3052-3060,共9页Chinese Journal of Tissue Engineering Research

基　　金：四川省科技计划重点研发项目(2019YFS0312),项目负责人:于湄;四川省科技计划应用基础研究项目(2020YJ0278),项目负责人:刘磊;国家自然科学基金区域创新发展联合基金(U21A20369),项目负责人:田卫东。

摘　　要：背景:目前许多研究者正在探索外泌体作为一种药物载体的新形式,即通过一系列生物工程技术对天然外泌体进行改造和修饰,通过装载的药物得到增强的特性和功能的工程化外泌体。目的:文章就工程化外泌体的制备策略、研究进展以及临床转化面临的挑战进行了综述。方法:检索PubMed数据库收录的相关文献以及FDA网站,英文检索词为“extracellular vesicles,exosomes,drug delivery,engineering,engineered,treatment,clinical translation,scale production,isolation,characterization,quality control,storage,safety”,最终纳入73篇文献与1篇网页声明进行归纳总结。结果与结论:①工程化外泌体可以通过细胞工程和外泌体工程制得,此2种策略制造的工程化外泌体的增强特性均已在基础研究中得到了验证,证实其具有巨大的临床应用前景,但同时均存在着一系列生物安全性、载药效率低下等问题亟待解决。②工程化外泌体已经在肿瘤、心血管疾病、组织再生与修复以及神经系统疾病等各个领域被证实具有良好的临床应用潜力,且均比天然外泌体展现出了更好的治疗效果及靶向性。③工程化外泌体的临床转化面临着诸多问题与挑战:各种常见细胞均可用于外泌体生产制造,细胞的代数及培养血清等变化也会导致外泌体的不同;扩大细胞培养规模是大量生产外泌体最直接的方法,不同的提取方法会影响其产量以及外泌体亚群的均一性,细胞培养的规模化以及分离提取流程需要标准化;合格的体外表征与量化可以预测载药外泌体系统的预期治疗潜力,需要进一步寻找开发外泌体量化以及分子和物理特征描述的金标准;外泌体产品需要额外程序进行把控,以确保外泌体终产品满足关键质量属性;冷冻干燥最有利于外泌体类治疗药物的商业化;监管机构至今尚未发布如何测试这些外泌体的安全性和有效性的指导意见,�BACKGROUND:Currently,exosomes were widely attracted as a new form of drug carrier by many researchers.Based on the modification by different bioengineering techniques,natural exosomes were engineered to obtain the enhanced exosomal characteristics and functions.OBJECTIVE:To review the preparation strategies,research progress and challenges in clinical translation of engineered exosomes.METHODS:We searched the articles on PubMed database and FDA online statements with the key words of“extracellular vesicles,exosomes,drug delivery,engineering,engineered,treatment,clinical translation,scale production,isolation,characterization,quality control,storage,safety”in English.Finally,73 articles and 1 statement met the criteria for review.RESULTS AND CONCLUSION:(1)Engineered exosomes can be produced by cell engineering and exosome engineering.The enhanced properties of engineered exosomes manufactured by the two strategies have been verified in basic research,which proves that they have great clinical application prospects.However,both of them have a series of problems such as biosafety and low drug loading efficiency that need to be solved.(2)Engineered exosomes have been proven to have great clinical application potential in various fields such as tumor,cardiovascular disease,tissue regeneration and repair,and nervous system diseases,and have shown better therapeutic effect and targeting ability than natural exosomes.(3)Clinical transformation of engineered exosomes faces many problems and challenges.All kinds of common cells can be used for exosome production and manufacturing.Changes in cell number and culture condition will lead to variation in exosomes.Expanding the scale of cell culture is the most direct method for mass production of exosomes.Different extraction methods will affect the yield and the homogeneity of exosome.The methods on scale culture,isolation and extraction need to be standardized.Characterization and quantification can predict the expected therapeutic potential of drug-loaded exosome systems

关 键 词：外泌体 生物工程 工程化外泌体 临床转化 规模化生产 分离提纯 成分表征 质量控制 储存稳定性 产品安全 

分 类 号：R459.9[医药卫生—治疗学] R363[医药卫生—临床医学] R364