外泌体靶向修饰的研究进展

Advances in targeted modification of extracellular vesicles

近年来,外泌体在生物医学领域的研究热度一直很高,尤其是随着研究的深入,其在作为治疗药物或载体的优势逐渐成为研究人员关注的热点.外泌体是几乎所有细胞都会分泌的一种细胞外囊泡,不同细胞类型分泌的外泌体也不同,其磷脂双分子层结构使它在细胞间的相容性很好,并具有一定的靶向性,在精准医疗领域具有良好的应用前景.外泌体的细胞外摄取机制复杂,主要通过内吞作用或膜融合的方式内化外泌体.为了提高外泌体对特定组织或器官的靶向特异性,现阶段的主流方法是通过修饰外泌体表面来实现.靶向修饰外泌体的方式主要分为生物化学方式和物理方式.但即使采用相同的靶向修饰方式作用于不同来源的外泌体,修饰后的工程化外泌体的生物性效应也表现不一.故此,标准化的外泌体表面靶向修饰联合载药可能成为今后研究的主流.本文阐述了外泌体的生物发生过程及细胞外摄取方式,综述了外泌体的靶向修饰方式,其中重点总结了各类外泌体靶向修饰方式的研究进展,并对外泌体靶向修饰的应用前景进行了展望.

In recent years,exosomes have become a hotspot in biomedical research.In-depth studies have revealed their advantages as therapeutic drugs or carriers.Exosomes are natural,nanoscale extracellular vesicles that can regulate cell-cell communication.Their cargoes mainly include DNA,RNA,glycoproteins,peptides,and other bioactive substances.Due to their phospholipid bilayer structure,exosomes exhibit good cell compatibility,low immunogenicity,a strong capacity to transfer bioactive substances,high biocompatibility,and specific targeting properties,rendering them favorable for precision medicine applications.Current research is mainly focused on engineering exosomes to achieve drug delivery,immune regulation,and potential biomarkers for disease diagnosis and surveillance.Exosomes have complex extracellular uptake mechanisms.Cells mainly internalize exosomes via endocytosis or membrane fusion,thereby exerting biological effects.However,the mechanism of extracellular exosome uptake is not yet fully understood.Several studies have investigated cholesterol-conjugated aptamers based on the mediating proteins involved in endocytosis and developed exosome-liposome hybrid vesicles loaded with targeting peptides based on applicable modes of membrane fusion.Due to different extents of enrichment,exosomes from different origins have different regulatory effects on different tissues and cells.To enhance the targeting activity of exosomes to specific tissues or organs,multiple researchers have developed a method that modifies the surfaces of natural exosomes,enhancing their desired molecular targeting activity.Although the advantages and disadvantages of several targeting modification methods have been investigated,most methods involve altering the morphology and size of the original exosomes.The engineered targeted exosomes exhibit heterogenous morphology,and the effects of morphological changes on the biological functions of exosomes warrant further investigation.The main exosome modification methods currently being investigated can be classified as either biochemical or physical.Biochemical methods include those involving genetic engineering,metabolic engineering,“click chemistry”,aptamer receptors,membrane peptide fusion,and peptide anchoring of CD63.Meanwhile,physical methods involve electrostatic interaction,hydrophobic interaction,magnetic guidance,ultrasonic guidance,and metal nanoparticle modification.The operational procedures used for the physical modification of targeted exosomes are relatively simple;however,the modification efficiency is low and unstable.Conversely,a high efficiency is achieved when exosomes are modified by biochemical methods;however,the operational procedures required for these methods are relatively difficult.These engineering methods are not independent,and the exosome modification process used may involve multiple methods.The modified exosomes are more enriched in target tissues and organs and have significantly better therapeutic effects than natural exosomes.However,when the same modification method is used on exosomes of different origins,the resulting engineered exosomes can exhibit different biological functions.Standardized exosome surface-targeted modification integrated with drug delivery may become a mainstream component of precision medicine research in the future.This article elaborates on the biogenesis process and extracellular uptake of exosomes and reviews exosometargeted modification methods.Furthermore,research progress in the field of exosome-targeted modification methods is summarized,and potential application prospects of exosometargeted modification are discussed.