工程化细胞外囊泡的设计合成与生物医学应用

Design and synthesis of engineered extracellular vesicles and their biomedical applications

近年来,细胞外囊泡因其与疾病发生发展密切相关而受到越来越广泛的关注。随着细胞外囊泡参与生命功能调控的机制被不断解析,利用细胞外囊泡作为药物载体,用于靶向治疗的工作也相继开展。细胞外囊泡作为药物载体,与人工载体相比,具有高生物相容性、低免疫原性和良好的生物膜融合能力,同时有着参与细胞通信的归巢效应等天然优势。然而,细胞外囊泡的生物医学应用也存在表面修饰复杂、包载能力差、产量较低等问题,导致使用范围严重受限。工程化细胞外囊泡是指对天然细胞外囊泡进行人工改造,使其能够特异性靶向受体细胞或组织,实现所包载功能分子的精准递送,并支撑可放大生产的模式,从而展现出广阔的生物医学应用前景。合成生物学技术的引入,可实现底盘细胞的从头设计再造,支撑细胞外囊泡的标准化、模块化合成。本文首先概括了工程化细胞外囊泡的表面修饰、工程化细胞外囊泡的功能分子包载的方法和应用;其次总结了工程化细胞外囊泡的生产制备,如提升细胞外囊泡产量的工程化策略、细胞外囊泡的放大生产与提取纯化等;最后展望了合成生物学通过改造底盘细胞基因组、人工设计囊泡表面蛋白、调控分子包载的细胞过程等定制化合成细胞外囊泡的前景。合成生物学技术的发展与使用可推动工程化细胞外囊泡的定制化设计与合成,将进一步精细控制其属性、提升其效能、拓展其应用,争取将其早日广泛应用于人类健康事业。

In recent years,extracellular vesicles have received increasing attention due to their close association with the occurrence and development of diseases.As mechanism underlying the regulation of extracellular vesicles on the development of diseases and other kinds of biological functions has been explored persistently,their utilization as drug carriers has also been tested by scientists for targeted therapy.Extracellular vesicles as drug carriers have several intrinsic advantages compared to artificial carriers,such as higher biocompatibility,lower immunogenicity,better capacity for biofilm fusion,and particular natural homing effect on intracellular communications.However,the biomedical applications of extracellular vesicles also face challenges with their complicated surface modification,poor drug loading capacity and low product yield.Engineered extracellular vesicles refer to the artificial modification of natural extracellular vesicles to particularly fit with target recipient cells or tissues,which can achieve precise delivery of contained functional molecules and support production at a large scale,thus showing a broad prospect for their biomedical applications.Synthetic biology technology can realize the de novo design and reengineering of chassis cells to support the standardized and modular synthesis of extracellular vesicles.This article first reviews the methods and applications of surface modification and functional molecule encapsulation of extracellular vesicles,and then summarizes strategies for their preparation and production,such as extraction,and purification.In the second section,we envision the role of synthetic biology in promoting the customized design and synthesis of engineered extracellular vesicles to further facilitate fine control on attributes,improve efficiency,and expand applications to make them widely used in human health as soon as possible.