乳外泌体的基本性质及其应用<sup>*</sup>

doi:10.13523/j.cb.2210010

中国生物工程杂志

2023, Vol. 43

Issue (2/3): 26-42 DOI: 10.13523/j.cb.2210010

新型药物递送系统研发与应用专题

乳外泌体的基本性质及其应用^*

郝东霞,田梦园,刘洋,李星,张媛^**(

)

陕西师范大学生命科学学院西北濒危药材资源开发国家工程实验室药用资源与天然药物化学教育部重点实验室西安 710119

Basic Properties and Applications of Milk Exosomes

HAO Dong-xia,TIAN Meng-yuan,LIU Yang,LI Xing,ZHANG Yuan^**(

)

Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, College of Life Sciences, Shaanxi Normal University, Xi’an 710119,China

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摘要：

乳外泌体是一种哺乳动物乳汁中广泛存在的细胞外囊泡,富含生物活性分子,可以将内容物转移到受体细胞。由于其潜在的药物口服递送潜力和良好的临床应用前景,近年来乳外泌体逐渐受到研究者的广泛关注。但是,从实验室到临床转化之间前仍存在一些问题,包括乳外泌体的产量、分离和纯化方法的异质性、装载效率等。从乳外泌体的组成结构、理化性质、分离纯化、装载药物和靶向递送等方面对目前的研究进行系统总结,并找出现有研究中的薄弱环节,为乳外泌体从实验阶段到临床治疗阶段的转化提供理论支持。

关键词： 乳外泌体; 药物递送载体; 分离纯化技术; 疾病治疗

Abstract:

Milk exosomes are ubiquitously extracellular vesicles in mammalian milk that are rich in bioactive molecules and transfer the contents to recipient cells. Due to their latent drug delivery potential and great clinical application prospects, milk exosomes have gradually attracted extensive attention of researchers in recent years. However, there are still some problems between the laboratory and clinical translation, including the yield of milk exosomes, heterogeneity of isolation, purification methods, and loading efficiency. This paper systematically summarizes the current research in terms of the composition, physicochemical properties, separation and purification, drug loading and targeted delivery of milk exosomes, and finds out the weak links in the existing research, so as to provide a theoretical support for the transformation from experimental stage to clinical treatment stage.

Key words: Milk exosomes Drug delivery vehicles Separation and purification technology Disease treatment

收稿日期: 2022-10-11 出版日期: 2023-03-31

ZTFLH:

Q819

基金资助: *陕西省重点产业创新链(群)-社会发展领域(2021ZDLSF03-09)

通讯作者: **张媛 E-mail: yuanzhang@snnu.edu.cn

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引用本文:

郝东霞, 田梦园, 刘洋, 李星, 张媛. 乳外泌体的基本性质及其应用^*[J]. 中国生物工程杂志, 2023, 43(2/3): 26-42.

HAO Dong-xia, TIAN Meng-yuan, LIU Yang, LI Xing, ZHANG Yuan. Basic Properties and Applications of Milk Exosomes. China Biotechnology, 2023, 43(2/3): 26-42.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2210010 或 https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I2/3/26

图1 乳外泌体的发现及研究历程

图2 外泌体的产生过程及其基本结构

富集的蛋白质种类	所含蛋白质的功能	蛋白质数量/种	差异表达的蛋白质/种	年份	参考文献
嗜乳脂蛋白(BTN1)、黄嘌呤脱氢酶 / 氧化酶(XDH)、乳黏蛋白(MFGE8)、围脂滴蛋白2(PLIN2)	参与细胞定位、多细胞生物过程、生物调控、发育过程、对刺激的反应	2 107	未显示	2012	[31]
心脏型脂肪酸结合蛋白(FABP3)、围脂滴蛋白2(PLIN2)、α - S1 - 酪蛋白(CSN1S1)、钙-整合素结合蛋白1、嗜乳脂蛋白亚家族 1 成员 A1(BTN1A1)、乳铁蛋白(LTF)	参与生物黏附、生物调节、细胞过程、发育、定位建立、胞吐作用、免疫过程、运动、代谢过程、多细胞过程、繁殖、对刺激的反应	2 350	1 490	2013	[32]
Ras相关蛋白Rab-5B、α-S1-酪蛋白(CSN1S1)、围脂滴蛋白2(PLIN2)、热休克蛋白 HSP 90-α(HSPA8)、Syntenin-1	参与刺激反应、定位、定位的建立、细胞成分组织、细胞成分生物发生、免疫系统过程、死亡、生物黏附、多生物过程和细胞杀伤	920	575	2017	[33]
κ-酪蛋白、黄嘌呤脱氢酶 / 氧化酶(XDH)、乳黏蛋白(MFGE8)和嗜乳脂蛋白亚家族 1 成员 A1 (BTN1A1)	参与细胞过程、发育、免疫系统、定位、代谢、生物黏附、生物调节、对刺激的反应、多细胞生物过程	94	86	2017	[34]
β -乳球蛋白(LGB)、牛孕激素相关子宫内膜蛋白(PAEP)、α -S1-酪蛋白 (CSN1S1)、α -S2-酪蛋白 (CSN1S2)、乳清蛋白α(LALBA)、乳黏蛋白 (MFGE8)、心脏型脂肪酸结合蛋白(FABP3)、嗜乳脂蛋白亚家族 1 成员 A1(BTN1A1)、黄嘌呤脱氢酶 / 氧化酶(XDH)、围脂滴蛋白2(PLIN2)、乳铁蛋白(LTF)	参与翻译起始、蛋白质修饰、过氧化物酶活性和代谢相关功能的调节	1 899	41	2017	[35]
Rab GTP 酶、整合素、嗜乳脂蛋白(BTN)、黄嘌呤氧化酶(XDH)、围脂滴蛋白2(PLIN2)、乳黏蛋白(MFGE8)、ESCRT 辅助蛋白 Alix	与先天免疫反应、炎症反应、急性期反应、血小板活化、细胞生长、补体活化、转运和细胞凋亡有关	1 372	4 443	2017	[36]
乳黏蛋白(MFGE8)、围脂滴蛋白2(PLIN2)、嗜乳脂蛋白(BTN)和黄嘌呤氧化酶/脱氢酶(XDH)、α-S1-酪蛋白 (CSN1S1)、κ-酪蛋白、β-酪蛋白、血小板糖蛋白4	大多数蛋白质在“结合”和“催化活性”下发挥作用,然后是“摩尔功能调节剂”和“结构分子活性”	239	186	2021	[37]

表1 乳外泌体富集蛋白质种类、差异蛋白质数量及其生物功能的总结

表2 乳外泌体分离方法的原理及比较

牛乳外泌体来源	粒径大小/nm	治疗效果	发表年份	参考文献
巴氏灭菌后的半脱脂牛乳	100~150	牛乳外泌体可降低抗胶原 IgG 2a 水平,并伴有脾 Th 1(Tbet)和 Th 17(RORγT)mRNA 表达的降低,缓解了 IL-1 Ra 缺陷小鼠自发性多关节炎和胶原诱导的关节炎	2015	[96]
市售半脱脂牛奶	100~150	牛乳外泌体携带有生物活性的 TGF-β,可诱导 Th 17 分化	2015	[20]
牛乳	—	牛乳外泌体中的亲酪蛋白(BTN)抑制髓鞘少突胶质细胞糖蛋白(MOG)诱导的实验性自身反应性脑脊髓炎 (EAE),可能会诱导多发性硬化患者的 MOG 特异性耐受	2015	[97]
牛初乳和成熟乳	30~150	牛乳外泌体富含免疫应答和生长相关蛋白,可能在调节婴儿的免疫应答和生长中具有重要作用	2017	[36]
牛乳	—	牛乳外泌体会改变成人和婴儿中嘌呤代谢物的血浆浓度和尿液排泄	2018	[98]
生牛乳	106.1	在结肠上皮细胞中,牛乳外泌体对正常和肿瘤细胞上皮细胞-间充质转化(EMT)的影响不同,正常胎儿上皮细胞形态和胶原蛋白表达发生改变,而肿瘤细胞无此改变	2019	[99]
牛乳	—	牛乳外泌体改变小鼠肠道微生物群落	2019	[100]
牛乳	约200	牛乳外泌体可增强杯状细胞活性并预防实验性坏死性小肠结肠炎的发展	2019	[101]
市售脱脂牛乳	—	牛乳外泌体可将 miRNA 转移到人类细胞并调节受体细胞基因表达	2020	[49]
牛乳外泌体来源	粒径大小/nm	治疗效果	发表年份	参考文献
市售脱脂牛乳	106.8 ± 3.4	牛乳外泌体可保护巨噬细胞抵抗顺铂诱导的细胞毒性	2020	[102]
市售脱脂牛乳	144±6.0	牛乳外泌体和 miRNA 可穿过胎盘促进小鼠胚胎存活	2020	[103]
巴氏灭菌后的脱脂牛乳	109±30.7	牛乳外泌体可能通过 TGF-β 信号通路发挥促进无疤痕伤口愈合的作用	2020	[104]
生牛乳	—	单独食用牛乳可能不会激活免疫细胞;然而,单独使用牛乳外泌体可在炎症条件下激活细胞	2020	[105]
牛乳	—	牛乳外泌体在溃疡性结肠炎的遗传小鼠模型中具有细胞保护/抗炎活性	2020	[106]
新鲜牛初乳	75.7	第一次在体内证实了牛乳外泌体对骨质疏松症的保护作用	2020	[107]
市售牛乳	80~190	乳外泌体中的 miR-2478 通过直接靶向 Rap 1a 而作为黑色素生成的调节剂。乳外泌体可降低黑色素含量、酪氨酸酶活性和黑色素生成相关基因的表达	2021	[108]
市售脱脂牛乳	67.23	牛乳外泌体对 IEC-6 细胞氧化应激具有保护作用	2021	[109]
脱脂牛乳	115.1±42.64	牛乳外泌体可降低氧化应激 IEC-6 细胞中嘌呤核苷酸的分解代谢,改善细胞能量状态,对氧化应激具有保护作用	2021	[110]
新鲜牛初乳	85.2	乳外泌体可通过调节肠道炎症免疫反应来减轻结肠炎症状,包括体重减轻、消化道出血和慢性腹泻	2022	[111]
新鲜生牛乳	132 ± 9.6	牛乳外泌体改善了肠道通透性、肠道结构和细胞增殖,在改善营养不良引起的肠黏膜萎缩和屏障功能障碍方面具有潜力	2021	[112]
生牛乳和市售牛乳	—	牛乳外泌体对肿瘤具有双重作用,在诱导原发肿瘤衰老的同时加速肿瘤转移	2021	[113]
市售脱脂乳	—	牛乳外泌体有助于小鼠神经元的最佳发育、空间学习和记忆,以及对红藻氨酸诱导的癫痫发作的抵抗	2022	[114]
牛乳	—	牛乳外泌体介导的 miR-31- 5p 通过促进血管生成促进糖尿病伤口愈合	2022	[115]
新鲜生牛乳	30~150	牛乳外泌体对登革热病毒和新城疫病毒的科马罗夫株(NDV-K)具有显著的抗病毒作用,但对人类免疫缺陷病毒感染无明显作用	2022	[116]
牛初乳	50~100	牛初乳外泌体可促进真皮乳头间叶细胞 (DP细胞)增殖,并可挽救双氢睾酮的表达,从而促进 DP 细胞增殖,具有治疗脱发的潜力	2022	[117]
牛乳	60~120	牛乳外泌体可通过促进血管生成减轻心肌纤维化大鼠的心肌纤维化,增强心功能	2022	[118]

表3 牛乳外泌体自身对疾病的治疗作用

表4 牛乳外泌体不同加载策略的比较

图3 乳外泌体修饰策略

[1]	Trams E G, Lauter C J, Norman Salem J Jr, et al. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1981, 645(1): 63-70. doi: 10.1016/0005-2736(81)90512-5
[2]	Admyre C, Johansson S M, Qazi K R, et al. Exosomes with immune modulatory features are present in human breast milk. Journal of Immunology (Baltimore, Md: 1950), 2007, 179(3): 1969-1978. doi: 10.4049/jimmunol.179.3.1969
[3]	Yamada T, Inoshima Y, Matsuda T, et al. Comparison of methods for isolating exosomes from bovine milk. The Journal of Veterinary Medical Science, 2012, 74(11): 1523-1525. doi: 10.1292/jvms.12-0032
[4]	Gu Y R, Li M Z, Wang T, et al. Lactation-related microRNA expression profiles of porcine breast milk exosomes. PLoS One, 2012, 7(8): e43691. doi: 10.1371/journal.pone.0043691
[5]	Modepalli V, Kumar A, Hinds L A, et al. Differential temporal expression of milk miRNA during the lactation cycle of the marsupial tammar wallaby (Macropus eugenii). BMC Genomics, 2014, 15(1): 1012. doi: 10.1186/1471-2164-15-1012
[6]	Yassin A M, Abdel Hamid M I, Farid O A, et al. Dromedary milk exosomes as mammary transcriptome nano-vehicle: their isolation, vesicular and phospholipidomic characterizations. Journal of Advanced Research, 2016, 7(5): 749-756. doi: 10.1016/j.jare.2015.10.003
[7]	Hock A, Miyake H, Li B, et al. Breast milk-derived exosomes promote intestinal epithelial cell growth. Journal of Pediatric Surgery, 2017, 52(5): 755-759. doi: S0022-3468(17)30065-9 pmid: 28188035
[8]	Sedykh S E, Purvinish L V, Monogarov A S, et al. Purified horse milk exosomes contain an unpredictable small number of major proteins. Biochimie Open, 2017, 4: 61-72. doi: 10.1016/j.biopen.2017.02.004 pmid: 29450143
[9]	Ma J D, Wang C D, Long K R, et al. Exosomal microRNAs in giant panda (Ailuropoda melanoleuca) breast milk: potential maternal regulators for the development of newborn cubs. Scientific Reports, 2017, 7: 3507. doi: 10.1038/s41598-017-03707-8 pmid: 28615713
[10]	Gao H N, Guo H Y, Zhang H, et al. Yak-milk-derived exosomes promote proliferation of intestinal epithelial cells in an hypoxic environment. Journal of Dairy Science, 2019, 102(2): 985-996. doi: S0022-0302(18)31093-2 pmid: 30580945
[11]	Quan S Y, Nan X M, Wang K, et al. Characterization of sheep milk extracellular vesicle-miRNA by sequencing and comparison with cow milk. Animals: An Open Access Journal from MDPI, 2020, 10(2): 331.
[12]	González M I, Martín-Duque P, Desco M, et al. Radioactive labeling of milk-derived exosomes with 99mTc and in vivo tracking by SPECT imaging. Nanomaterials (Basel, Switzerland), 2020, 10(6): 1062.
[13]	Li S Y, Tang Y, Dou Y S. The potential of milk-derived exosomes for drug delivery. Current Drug Delivery, 2021, 18(6): 688-699. doi: 10.2174/1567201817666200817112503
[14]	Zempleni J, Sukreet S, Zhou F, et al. Milk-derived exosomes and metabolic regulation. Annual Review of Animal Biosciences, 2019, 7: 245-262. doi: 10.1146/annurev-animal-020518-115300 pmid: 30285461
[15]	Chen X, Liang H W, Zhang J F, et al. Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein & Cell, 2012, 3(1): 28-37.
[16]	He C J, Zheng S, Luo Y, et al. Exosome theranostics: biology and translational medicine. Theranostics, 2018, 8(1): 237-255. doi: 10.7150/thno.21945 pmid: 29290805
[17]	Kleinjan M, van Herwijnen M J, Libregts S F, et al. Regular industrial processing of bovine milk impacts the integrity and molecular composition of extracellular vesicles. The Journal of Nutrition, 2021, 151(6): 1416-1425. doi: 10.1093/jn/nxab031
[18]	Benmoussa A, Lee C H C, Laffont B, et al. Commercial dairy cow milk microRNAs resist digestion under simulated gastrointestinal tract conditions. The Journal of Nutrition, 2016, 146(11): 2206-2215. doi: 10.3945/jn.116.237651
[19]	Yu S R, Zhao Z H, Sun L M, et al. Fermentation results in quantitative changes in milk-derived exosomes and different effects on cell growth and survival. Journal of Agricultural and Food Chemistry, 2017, 65(6): 1220-1228. doi: 10.1021/acs.jafc.6b05002 pmid: 28085261
[20]	Pieters B C H, Arntz O J, Bennink M B, et al. Commercial cow milk contains physically stable extracellular vesicles expressing immunoregulatory TGF-Β. PLoS One, 2015, 10(3): e0121123. doi: 10.1371/journal.pone.0121123
[21]	Mathivanan S, Fahner C J, Reid G E, et al. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Research, 2012, 40(D1): D1241-D1244.
[22]	Kim D K, Lee J, Kim S R, et al. EVpedia: a community web portal for extracellular vesicles research. Bioinformatics, 2015, 31(6): 933-939. doi: 10.1093/bioinformatics/btu741
[23]	Kalra H, Simpson R J, Ji H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biology, 2012, 10(12): e1001450. doi: 10.1371/journal.pbio.1001450
[24]	Maity S, Bhat A H, Giri K, et al. BoMiProt: a database of bovine milk proteins. Journal of Proteomics, 2020, 215: 103648. doi: 10.1016/j.jprot.2020.103648
[25]	Savina A, Fader C M, Damiani M T, et al. Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic (Copenhagen, Denmark), 2005, 6(2): 131-143. doi: 10.1111/j.1600-0854.2004.00257.x
[26]	Hurley J H, Odorizzi G. Get on the exosome bus with ALIX. Nature Cell Biology, 2012, 14(7): 654-655. doi: 10.1038/ncb2530 pmid: 22743708
[27]	Lässer C, Alikhani V S, Ekström K, et al. Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. Journal of Translational Medicine, 2011, 9: 9. doi: 10.1186/1479-5876-9-9 pmid: 21235781
[28]	Pols M S, Klumperman J. Trafficking and function of the tetraspanin CD63. Experimental Cell Research, 2009, 315(9): 1584-1592. doi: 10.1016/j.yexcr.2008.09.020 pmid: 18930046
[29]	Bandres E, Bitarte N, Arias F, et al. MicroRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research, 2009, 15(7): 2281-2290. doi: 10.1158/1078-0432.CCR-08-1818
[30]	Sedykh S E, Burkova E E, Purvinsh L V, et al. Milk exosomes: isolation, biochemistry, morphology, and perspectives of use. Extracellular Vesicles and Their Importance in Human Health, 2020, 3: DOI: 10.5772/intechopen.85416. doi: 10.5772/intechopen.85416
[31]	Reinhardt T A, Lippolis J D, Nonnecke B J, et al. Bovine milk exosome proteome. Journal of Proteomics, 2012, 75(5): 1486-1492. doi: 10.1016/j.jprot.2011.11.017 pmid: 22129587
[32]	Reinhardt T A, Sacco R E, Nonnecke B J, et al. Bovine milk proteome: quantitative changes in normal milk exosomes, milk fat globule membranes and whey proteomes resulting from Staphylococcus aureus mastitis. Journal of Proteomics, 2013, 82: 141-154. doi: 10.1016/j.jprot.2013.02.013 pmid: 23459212
[33]	Yang M, Song D H, Cao X Y, et al. Comparative proteomic analysis of milk-derived exosomes in human and bovine colostrum and mature milk samples by iTRAQ-coupled LC-MS/MS. Food Research International, 2017, 92: 17-25. doi: S0963-9969(16)30590-7 pmid: 28290293
[34]	Koh Y Q, Peiris H N, Vaswani K, et al. Characterization of exosomes from body fluids of dairy cows. Journal of Animal Science, 2017, 95(9): 3893-3904. doi: 10.2527/jas2017.1727 pmid: 28992005
[35]	Benmoussa A, Gotti C, Bourassa S, et al. Identification of protein markers for extracellular vesicle (EV) subsets in cow’s milk. Journal of Proteomics, 2019, 192: 78-88. doi: 10.1016/j.jprot.2018.08.010
[36]	Samuel M, Chisanga D, Liem M, et al. Bovine milk-derived exosomes from colostrum are enriched with proteins implicated in immune response and growth. Scientific Reports, 2017, 7: 5933. doi: 10.1038/s41598-017-06288-8 pmid: 28725021
[37]	Vaswani K M, Peiris H, Koh Y Q, et al. A complete proteomic profile of human and bovine milk exosomes by liquid chromatography mass spectrometry. Expert Review of Proteomics, 2021, 18(8): 719-735. doi: 10.1080/14789450.2021.1980389 pmid: 34551655
[38]	Liao Y L, Du X G, Li J, et al. Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Molecular Nutrition & Food Research, 2017, 61(11): 10.1002/mnfr.201700082.
[39]	Izumi H, Kosaka N, Shimizu T, et al. Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. Journal of Dairy Science, 2012, 95(9): 4831-4841. doi: S0022-0302(12)00497-3 pmid: 22916887
[40]	Le T T, Van de Wiele T, Do T N H, et al. Stability of milk fat globule membrane proteins toward human enzymatic gastrointestinal digestion. Journal of Dairy Science, 2012, 95(5): 2307-2318. doi: 10.3168/jds.2011-4947 pmid: 22541459
[41]	Benmoussa A, Ly S, Shan S T, et al. A subset of extracellular vesicles carries the bulk of microRNAs in commercial dairy cow’s milk. Journal of Extracellular Vesicles, 2017, 6(1): 1401897. doi: 10.1080/20013078.2017.1401897
[42]	Betker J L, Angle B M, Graner M W, et al. The potential of exosomes from cow milk for oral delivery. J Pharm Sci, 2019, 108(4): 1496-1505. doi: 10.1016/j.xphs.2018.11.022
[43]	Pallesen L T, Pedersen L R L, Petersen T E, et al. Characterization of carbohydrate structures of bovine MUC15 and distribution of the mucin in bovine milk. Journal of Dairy Science, 2007, 90(7): 3143-3152. pmid: 17582096
[44]	Uhlén M, Fagerberg L, Hallström B M, et al. Proteomics. Tissue-based map of the human proteome. Science, 2015, 347(6220): 1260419. doi: 10.1126/science.1260419
[45]	Chen W Y, Wang R, Li D, et al. Comprehensive analysis of the glycome and glycoproteome of bovine milk-derived exosomes. Journal of Agricultural and Food Chemistry, 2020, 68(45): 12692-12701. doi: 10.1021/acs.jafc.0c04605 pmid: 33137256
[46]	Chauhan S, Danielson S, Clements V, et al. Surface glycoproteins of exosomes shed by myeloid-derived suppressor cells contribute to function. Journal of Proteome Research, 2017, 16(1): 238-246. doi: 10.1021/acs.jproteome.6b00811 pmid: 27728760
[47]	Sukreet S, Silva B V R E, Adamec J, et al. Galactose and sialo-galactose modifications in glycoproteins on the surface of bovine milk exosome are essential for exosome uptake in non-bovine species (OR34-07-19). Current Developments in Nutrition, 2019, 3(Supplement_1): nzz031.OR34-7.
[48]	Zeng B, Chen T, Luo J Y, et al. Biological characteristics and roles of noncoding RNAs in milk-derived extracellular vesicles. Advances in Nutrition, 2021, 12(3): 1006-1019. doi: 10.1093/advances/nmaa124 pmid: 33080010
[49]	Benmoussa A, Laugier J, Beauparlant C J, et al. Complexity of the microRNA transcriptome of cow milk and milk-derived extracellular vesicles isolated via differential ultracentrifugation. Journal of Dairy Science, 2020, 103(1): 16-29. doi: S0022-0302(19)30946-4 pmid: 31677838
[50]	Yun B, Kim Y, Park D J, et al. Comparative analysis of dietary exosome-derived microRNAs from human, bovine and caprine colostrum and mature milk. Journal of Animal Science and Technology, 2021, 63(3): 593-602. doi: 10.5187/jast.2021.e39 pmid: 34189507
[51]	Tian L, Zhang L, Cui Y J, et al. MiR-142-3p regulates milk synthesis and structure of murine mammary glands via PRLR-mediated multiple signaling pathways. Journal of Agricultural and Food Chemistry, 2019, 67(34): 9532-9542. doi: 10.1021/acs.jafc.9b03734 pmid: 31369265
[52]	Chen Z, Chu S F, Wang X L, et al. MicroRNA-106b regulates milk fat metabolism via ATP binding cassette subfamily A member 1 (ABCA1) in bovine mammary epithelial cells. Journal of Agricultural and Food Chemistry, 2019, 67(14): 3981-3990. doi: 10.1021/acs.jafc.9b00622 pmid: 30892026
[53]	Zhang M Q, Gao J L, Liao X D, et al. MiR-454 regulates triglyceride synthesis in bovine mammary epithelial cells by targeting PPAR-Γ. Gene, 2019, 691: 1-7. doi: 10.1016/j.gene.2018.12.048
[54]	Wang Y J, Guo W L, Tang K Q, et al. Bta-miR-34b regulates milk fat biosynthesis by targeting mRNA decapping enzyme 1A (DCP1A) in cultured bovine mammary epithelial cells. Journal of Animal Science, 2019, 97(9): 3823-3831. doi: 10.1093/jas/skz230
[55]	Chen Z, Chu S F, Wang X L, et al. MiR-16a regulates milk fat metabolism by targeting large tumor suppressor kinase 1 (LATS1) in bovine mammary epithelial cells. Journal of Agricultural and Food Chemistry, 2019, 67(40): 11167-11178. doi: 10.1021/acs.jafc.9b04883 pmid: 31542928
[56]	Cao Q Q, Li H H, Liu X, et al. MiR-24-3p regulates cell proliferation and milk protein synthesis of mammary epithelial cells through menin in dairy cows. Journal of Cellular Physiology, 2019, 234(2): 1522-1533. doi: 10.1002/jcp.27017 pmid: 30221364
[57]	Sun J J, Aswath K, Schroeder S G, et al. MicroRNA expression profiles of bovine milk exosomes in response to Staphylococcus aureus infection. BMC Genomics, 2015, 16: 806. doi: 10.1186/s12864-015-2044-9
[58]	Guo Z J, Karunatilaka K S, Rueda D. Single-molecule analysis of protein-free U2-U6 snRNAs. Nature Structural & Molecular Biology, 2009, 16(11): 1154-1159. doi: 10.1038/nsmb.1672
[59]	Hughes J M X. Eukaryotic ribosomal RNA: the recent excitement in the nucleotide modification problem. Chromosoma, 1997, 105(7): 391-400. doi: 10.1007/BF02510475
[60]	Izumi H, Tsuda M, Sato Y, et al. Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. Journal of Dairy Science, 2015, 98(5): 2920-2933. doi: 10.3168/jds.2014-9076 pmid: 25726110
[61]	Valadi H, Ekström K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 2007, 9(6): 654-659. doi: 10.1038/ncb1596 pmid: 17486113
[62]	Kanada M, Bachmann M H, Hardy J W, et al. Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(12): E1433-E1442.
[63]	Kusuma R J, Manca S, Friemel T, et al. Human vascular endothelial cells transport foreign exosomes from cow’s milk by endocytosis. American Journal of Physiology Cell Physiology, 2016, 310(10): C800-C807. doi: 10.1152/ajpcell.00169.2015
[64]	Thompson A E. The immune system. JAMA, 2015, 313(16): 1686. doi: 10.1001/jama.2015.2940 pmid: 25919540
[65]	Batagov A O, Kurochkin I V. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3’-untranslated regions. Biology Direct, 2013, 8: 12. doi: 10.1186/1745-6150-8-12 pmid: 23758897
[66]	Balaj L, Lessard R, Dai L X, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nature Communications, 2011, 2: 180. doi: 10.1038/ncomms1180 pmid: 21285958
[67]	Kahlert C, Melo S A, Protopopov A, et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. Journal of Biological Chemistry, 2014, 289(7): 3869-3875. doi: 10.1074/jbc.C113.532267
[68]	Thakur B K, Zhang H Y, Becker A, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Research, 2014, 24(6): 766-769. doi: 10.1038/cr.2014.44 pmid: 24710597
[69]	Subra C, Grand D, Laulagnier K, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. Journal of Lipid Research, 2010, 51(8): 2105-2120. doi: 10.1194/jlr.M003657 pmid: 20424270
[70]	Skotland T, Sandvig K, Llorente A. Lipids in exosomes: current knowledge and the way forward. Progress in Lipid Research, 2017, 66: 30-41. doi: S0163-7827(16)30049-2 pmid: 28342835
[71]	van Meer G, Voelker D R, Feigenson G W. Membrane lipids: where they are and how they behave. Nature Reviews Molecular Cell Biology, 2008, 9(2): 112-124. doi: 10.1038/nrm2330 pmid: 18216768
[72]	Clark M R. Flippin’ lipids. Nature Immunology, 2011, 12(5): 373-375. doi: 10.1038/ni.2024
[73]	Hankins H M, Baldridge R D, Xu P, et al. Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution. Traffic (Copenhagen, Denmark), 2015, 16(1): 35-47. doi: 10.1111/tra.2015.16.issue-1
[74]	Brown B A, Zeng X Y, Todd A R, et al. Charge detection mass spectrometry measurements of exosomes and other extracellular particles enriched from bovine milk. Analytical Chemistry, 2020, 92(4): 3285-3292. doi: 10.1021/acs.analchem.9b05173 pmid: 31989813
[75]	Zonneveld M I, Brisson A R, van Herwijnen M J C, et al. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. Journal of Extracellular Vesicles, 2014, 3: DOI: 10.3402/jev.v3.24215. doi: 10.3402/jev.v3.24215
[76]	Yang M, Cong M, Peng X M, et al. Quantitative proteomic analysis of milk fat globule membrane (MFGM) proteins in human and bovine colostrum and mature milk samples through iTRAQ labeling. Food & Function, 2016, 7(5): 2438-2450.
[77]	Arranz E, Corredig M. Invited review: Milk phospholipid vesicles, their colloidal properties, and potential as delivery vehicles for bioactive molecules. Journal of Dairy Science, 2017, 100(6): 4213-4222. doi: S0022-0302(17)30259-X pmid: 28343627
[78]	Vaswani K, Mitchell M D, Holland O J, et al. A method for the isolation of exosomes from human and bovine milk. Journal of Nutrition and Metabolism, 2019, 2019: 5764740.
[79]	Hata T, Murakami K, Nakatani H, et al. Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochemical and Biophysical Research Communications, 2010, 396(2): 528-533. doi: 10.1016/j.bbrc.2010.04.135 pmid: 20434431
[80]	Vaswani K, Koh Y Q, Almughlliq F B, et al. A method for the isolation and enrichment of purified bovine milk exosomes. Reproductive Biology, 2017, 17(4): 341-348. doi: S1642-431X(17)30159-6 pmid: 29030127
[81]	Sukreet S, Braga C P, An T T, et al. Isolation of extracellular vesicles from byproducts of cheesemaking by tangential flow filtration yields heterogeneous fractions of nanoparticles. Journal of Dairy Science, 2021, 104(9): 9478-9493. doi: 10.3168/jds.2021-20300 pmid: 34218910
[82]	Yamauchi M, Shimizu K, Rahman M, et al. Efficient method for isolation of exosomes from raw bovine milk. Drug Development and Industrial Pharmacy, 2019, 45(3): 359-364. doi: 10.1080/03639045.2018.1539743 pmid: 30366501
[83]	Li P, Kaslan M, Lee S H, et al. Progress in exosome isolation techniques. Theranostics, 2017, 7(3): 789-804. doi: 10.7150/thno.18133 pmid: 28255367
[84]	Benmoussa A, Michel S, Gilbert C, et al. Isolating multiple extracellular vesicles subsets, including exosomes and membrane vesicles, from bovine milk using sodium citrate and differential ultracentrifugation. Bio-protocol, 2020, 10(11): e3636. doi: 10.21769/BioProtoc.3636 pmid: 33659307
[85]	Bess J W Jr, Gorelick R J, Bosche W J, et al. Microvesicles are a source of contaminating cellular proteins found in purified HIV-1 preparations. Virology, 1997, 230(1): 134-144. pmid: 9126269
[86]	Cantin R, Diou J, Bélanger D, et al. Discrimination between exosomes and HIV-1: purification of both vesicles from cell-free supernatants. Journal of Immunological Methods, 2008, 338(1-2): 21-30. doi: 10.1016/j.jim.2008.07.007 pmid: 18675270
[87]	Leberman R. The isolation of plant viruses by means of “simple” coacervates. Virology, 1966, 30(3): 341-347. pmid: 5921640
[88]	Zeringer E, Barta T, Li M, et al. Strategies for isolation of exosomes. Cold Spring Harbor Protocols, 2015, 2015(4): 319-323. doi: 10.1101/pdb.top074476 pmid: 25834266
[89]	Kim D K, Nishida H, An S Y, et al. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(1): 170-175.
[90]	Blans K, Hansen M S, Sørensen L V, et al. Pellet-free isolation of human and bovine milk extracellular vesicles by size-exclusion chromatography. Journal of Extracellular Vesicles, 2017, 6(1): 1294340. doi: 10.1080/20013078.2017.1294340
[91]	Haraszti R A, Miller R, Stoppato M, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Molecular Therapy, 2018, 26(12): 2838-2847. doi: S1525-0016(18)30456-8 pmid: 30341012
[92]	李莹, 陈璟瑶, 赵军英, 等. 乳源外泌体的研究进展. 食品工业科技, 2022, 43(22): 406-413.
	Li Y, Chen J Y, Zhao J Y, et al. Research progress in milk-derived exosomes. Science and Technology of Food Industry, 2022, 43(22): 406-413.
[93]	Munagala R, Aqil F, Jeyabalan J, et al. Bovine milk-derived exosomes for drug delivery. Cancer Letters, 2016, 371(1): 48-61. doi: 10.1016/j.canlet.2015.10.020 pmid: 26604130
[94]	Koga K, Matsumoto K, Akiyoshi T, et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Research, 2005, 25(6A): 3703-3707. pmid: 16302729
[95]	Melo S A, Luecke L B, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 2015, 523(7559): 177-182. doi: 10.1038/nature14581
[96]	Arntz O J, Pieters B C H, Oliveira M C, et al. Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models. Molecular Nutrition & Food Research, 2015, 59(9): 1701-1712.
[97]	Mokarizadeh A, Hassanzadeh K, Abdi M, et al. Transdermal delivery of bovine milk vesicles in patients with multiple sclerosis: a novel strategy to induce MOG-specific tolerance. Medical Hypotheses, 2015, 85(2): 141-144. doi: 10.1016/j.mehy.2015.04.019 pmid: 25986518
[98]	Aguilar-Lozano A, Baier S, Grove R, et al. Concentrations of purine metabolites are elevated in fluids from adults and infants and in livers from mice fed diets depleted of bovine milk exosomes and their RNA cargos. The Journal of Nutrition, 2018, 148(12): 1886-1894. doi: 10.1093/jn/nxy223
[99]	Reif S, Elbaum Shiff Y, Golan-Gerstl R. Milk-derived exosomes (MDEs) have a different biological effect on normal fetal colon epithelial cells compared to colon tumor cells in a miRNA-dependent manner. Journal of Translational Medicine, 2019, 17(1): 325. doi: 10.1186/s12967-019-2072-3
[100]	Zhou F, Paz H A, Sadri M, et al. Dietary bovine milk exosomes elicit changes in bacterial communities in C57BL/ 6 mice. American Journal of Physiology Gastrointestinal and Liver Physiology, 2019, 317(5): G618-G624. doi: 10.1152/ajpgi.00160.2019
[101]	Li B, Hock A, Wu R Y, et al. Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS One, 2019, 14(1): e0211431. doi: 10.1371/journal.pone.0211431
[102]	Matic S, D’Souza D H, Wu T, et al. Bovine milk exosomes affect proliferation and protect macrophages against cisplatin-induced cytotoxicity. Immunological Investigations, 2020, 49(7): 711-725. doi: 10.1080/08820139.2020.1769647
[103]	Sadri M, Shu J, Kachman S D, et al. Milk exosomes and miRNA cross the placenta and promote embryo survival in mice. Reproduction (Cambridge, England), 2020, 160(4): 501-509. doi: 10.1530/REP-19-0521
[104]	Ahn G, Kim Y H, Ahn J Y. Multifaceted effects of milk-exosomes (Mi-Exo) as a modulator of scar-free wound healing. Nanoscale Advances, 2020, 3(2): 528-537. doi: 10.1039/D0NA00665C
[105]	Komine-Aizawa S, Ito S, Aizawa S, et al. Cow milk exosomes activate NK cells and γδT cells in human PBMCs in vitro. Immunological Medicine, 2020, 43(4): 161-170. doi: 10.1080/25785826.2020.1791400
[106]	Stremmel W, Weiskirchen R, Melnik B C. Milk exosomes prevent intestinal inflammation in a genetic mouse model of ulcerative colitis: a pilot experiment. Inflammatory Intestinal Diseases, 2020, 5(3): 117-123. doi: 10.1159/000507626 pmid: 32999884
[107]	Yun B, Maburutse B E, Kang M, et al. Short communication: Dietary bovine milk-derived exosomes improve bone health in an osteoporosis-induced mouse model. Journal of Dairy Science, 2020, 103(9): 7752-7760. doi: S0022-0302(20)30493-8 pmid: 32622594
[108]	Bae I S, Kim S H. Milk exosome-derived microRNA-2478 suppresses melanogenesis through the Akt-GSK3β pathway. Cells, 2021, 10(11): 2848. doi: 10.3390/cells10112848
[109]	Wang L F, Shi Z X, Wang X Y, et al. Protective effects of bovine milk exosomes against oxidative stress in IEC-6 cells. European Journal of Nutrition, 2021, 60(1): 317-327. doi: 10.1007/s00394-020-02242-z
[110]	Wang L F, Wang X Y, Shi Z X, et al. Bovine milk exosomes attenuate the alteration of purine metabolism and energy status in IEC-6 cells induced by hydrogen peroxide. Food Chemistry, 2021, 350: 129142. doi: 10.1016/j.foodchem.2021.129142
[111]	Han G, Cho H, Kim H, et al. Bovine colostrum derived-exosomes prevent dextran sulfate sodium-induced intestinal colitis via suppression of inflammation and oxidative stress. Biomaterials Science, 2022, 10(8): 2076-2087. doi: 10.1039/D1BM01797G
[112]	Maghraby M K, Li B, Chi L J, et al. Extracellular vesicles isolated from milk can improve gut barrier dysfunction induced by malnutrition. Scientific Reports, 2021, 11: 7635. doi: 10.1038/s41598-021-86920-w pmid: 33828139
[113]	Samuel M, Fonseka P, Sanwlani R, et al. Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis. Nature Communications, 2021, 12: 3950. doi: 10.1038/s41467-021-24273-8 pmid: 34168137
[114]	Zhou F, Ebea P, Mutai E, et al. Small extracellular vesicles in milk cross the blood-brain barrier in murine cerebral cortex endothelial cells and promote dendritic complexity in the Hippocampus and brain function in C57BL/6J mice. Frontiers in Nutrition, 2022, 9: 838543. doi: 10.3389/fnut.2022.838543
[115]	Yan C Q, Chen J, Wang C, et al. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Delivery, 2022, 29(1): 214-228. doi: 10.1080/10717544.2021.2023699 pmid: 34985397
[116]	Yenuganti V R, Afroz S, Khan R A, et al. Milk exosomes elicit a potent anti-viral activity against dengue virus. Journal of Nanobiotechnology, 2022, 20(1): 317. doi: 10.1186/s12951-022-01496-5 pmid: 35794557
[117]	Kim H, Jang Y, Kim E H, et al. Potential of colostrum-derived exosomes for promoting hair regeneration through the transition from telogen to anagen phase. Frontiers in Cell and Developmental Biology, 2022, 10: 815205. doi: 10.3389/fcell.2022.815205
[118]	Zhang C L, Lu X X, Hu J J, et al. Bovine milk exosomes alleviate cardiac fibrosis via enhancing angiogenesis in vivo and in vitro. Journal of Cardiovascular Translational Research, 2022, 15(3): 560-570. doi: 10.1007/s12265-021-10174-0
[119]	Sharma A, Kumar M, Aich J, et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(14): 5761-5766.
[120]	Qin L M, Chen Y S, Niu Y N, et al. A deep investigation into the adipogenesis mechanism: profile of microRNAs regulating adipogenesis by modulating the canonical Wnt/beta-catenin signaling pathway. BMC Genomics, 2010, 11: 320. doi: 10.1186/1471-2164-11-320 pmid: 20492721
[121]	Oishi N, Wang X W. Novel therapeutic strategies for targeting liver cancer stem cells. International Journal of Biological Sciences, 2011, 7(5): 517-535. doi: 10.7150/ijbs.7.517 pmid: 21552419
[122]	Näslund T I, Paquin-Proulx D, Paredes P T, et al. Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells. AIDS (London, England), 2014, 28(2): 171-180. doi: 10.1097/QAD.0000000000000159
[123]	李婷, 田洪磊, 杨兴斌. miRNAG肠道微生物轴与机体健康. 未来食品科学, 2022(1): 54-64.
	Li T, Tian H L, Yang X B. miRNA-gut microbiota axis and body health. Future Food Science, 2022(1): 54-64.
[124]	Reif S, Elbaum-Shiff Y, Koroukhov N, et al. Cow and human milk-derived exosomes ameliorate colitis in DSS murine model. Nutrients, 2020, 12(9): 2589. doi: 10.3390/nu12092589
[125]	Pieters B C H, Arntz O J, Aarts J, et al. Bovine milk-derived extracellular vesicles inhibit catabolic and inflammatory processes in cartilage from osteoarthritis patients. Molecular Nutrition & Food Research, 2022, 66(6): e2100764.
[126]	Fernandez-Fernandez A, Manchanda R, McGoron A J. Theranostic applications of nanomaterials in cancer: drug delivery, image-guided therapy, and multifunctional platforms. Applied Biochemistry and Biotechnology, 2011, 165(7): 1628-1651. doi: 10.1007/s12010-011-9383-z
[127]	Jesorka A, Orwar O. Liposomes: technologies and analytical applications. Annual Review of Analytical Chemistry (Palo Alto, Calif), 2008, 1: 801-832. doi: 10.1146/anchem.2008.1.issue-1
[128]	Zhong J, Xia B Z, Shan S B, et al. High-quality milk exosomes as oral drug delivery system. Biomaterials, 2021, 277: 121126. doi: 10.1016/j.biomaterials.2021.121126
[129]	Vashisht M, Rani P, Onteru S K, et al. Curcumin encapsulated in milk exosomes resists human digestion and possesses enhanced intestinal permeability in vitro. Applied Biochemistry and Biotechnology, 2017, 183(3): 993-1007. doi: 10.1007/s12010-017-2478-4 pmid: 28466459
[130]	Zhao X Y, Wu D L, Ma X D, et al. Exosomes as drug carriers for cancer therapy and challenges regarding exosome uptake. Biomedicine & Pharmacotherapy, 2020, 128: 110237. doi: 10.1016/j.biopha.2020.110237
[131]	Yuan D F, Zhao Y L, Banks W A, et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials, 2017, 142: 1-12. doi: S0142-9612(17)30461-1 pmid: 28715655
[132]	Haney M J, Klyachko N L, Zhao Y L, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. Journal of Controlled Release, 2015, 207: 18-30. doi: 10.1016/j.jconrel.2015.03.033
[133]	Kim M S, Haney M J, Zhao Y L, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine: Nanotechnology, Biology and Medicine, 2016, 12(3): 655-664. doi: 10.1016/j.nano.2015.10.012
[134]	Jang S C, Kim O Y, Yoon C M, et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano, 2013, 7(9): 7698-7710. doi: 10.1021/nn402232g pmid: 24004438
[135]	Aqil F, Munagala R, Jeyabalan J, et al. Milk exosomes-natural nanoparticles for siRNA delivery. Cancer Letters, 2019, 449: 186-195. doi: 10.1016/j.canlet.2019.02.011
[136]	Zhuang X Y, Xiang X Y, Grizzle W, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Molecular Therapy, 2011, 19(10): 1769-1779. doi: 10.1038/mt.2011.164 pmid: 21915101
[137]	Tian T, Zhu Y L, Zhou Y Y, et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. Journal of Biological Chemistry, 2014, 289(32): 22258-22267. doi: 10.1074/jbc.M114.588046 pmid: 24951588
[138]	Liang G F, Zhu Y L, Ali D J, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. Journal of Nanobiotechnology, 2020, 18(1): 10. doi: 10.1186/s12951-019-0563-2 pmid: 31918721
[139]	Jhan Y Y, Prasca-Chamorro D, Palou Zuniga G, et al. Engineered extracellular vesicles with synthetic lipids via membrane fusion to establish efficient gene delivery. International Journal of Pharmaceutics, 2020, 573: 118802. doi: 10.1016/j.ijpharm.2019.118802
[140]	Lamichhane T N, Jeyaram A, Patel D B, et al. Oncogene knockdown via active loading of small RNAs into extracellular vesicles by sonication. Cellular and Molecular Bioengineering, 2016, 9(3): 315-324. pmid: 27800035
[141]	Podolak I, Galanty A, Sobolewska D. Saponins as cytotoxic agents: a review. Phytochemistry Reviews, 2010, 9(3): 425-474. pmid: 20835386
[142]	Alvarez-Erviti L, Seow Y, Yin H F, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 2011, 29(4): 341-345. doi: 10.1038/nbt.1807 pmid: 21423189
[143]	Yang Y, Hong Y, Cho E, et al. Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery. Journal of Extracellular Vesicles, 2018, 7(1): 1440131. doi: 10.1080/20013078.2018.1440131
[144]	Smyth T, Petrova K, Payton N M, et al. Surface functionalization of exosomes using click chemistry. Bioconjugate Chemistry, 2014, 25(10): 1777-1784. doi: 10.1021/bc500291r pmid: 25220352
[145]	Nie W D, Wu G H, Zhang J F, et al. Responsive exosome nano-bioconjugates for synergistic cancer therapy. Angewandte Chemie (International Ed in English), 2020, 59(5): 2018-2022. doi: 10.1002/anie.v59.5
[146]	Kim M S, Haney M J, Zhao Y L, et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine: Nanotechnology, Biology and Medicine, 2018, 14(1): 195-204. doi: 10.1016/j.nano.2017.09.011
[147]	Wang Y Y, Chen X J, Tian B Q, et al. Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer. Theranostics, 2017, 7(5): 1360-1372. doi: 10.7150/thno.16532 pmid: 28435471
[148]	Zou J M, Shi M L, Liu X J, et al. Aptamer-functionalized exosomes: elucidating the cellular uptake mechanism and the potential for cancer-targeted chemotherapy. Analytical Chemistry, 2019, 91(3): 2425-2430. doi: 10.1021/acs.analchem.8b05204 pmid: 30620179
[149]	Cheng H, Fan J H, Zhao L P, et al. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials, 2019, 211: 14-24. doi: S0142-9612(19)30268-6 pmid: 31078049
[150]	Yang Y, Hong Y, Nam G H, et al. Virus-mimetic fusogenic exosomes for direct delivery of integral membrane proteins to target cell membranes. Advanced Materials (Deerfield Beach, Fla), 2017, 29(13): 1605604. doi: 10.1002/adma.201605604
[151]	Lin Y, Wu J H, Gu W H, et al. Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas 9 system in MSCs. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 2018, 5(4): 1700611.
[152]	Rayamajhi S, Nguyen T D T, Marasini R, et al. Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery. Acta Biomaterialia, 2019, 94: 482-494. doi: S1742-7061(19)30381-2 pmid: 31129363
[153]	Piffoux M, Silva A K A, Wilhelm C, et al. Modification of extracellular vesicles by fusion with liposomes for the design of personalized biogenic drug delivery systems. ACS Nano, 2018, 12(7): 6830-6842. doi: 10.1021/acsnano.8b02053 pmid: 29975503
[154]	Aqil F, Munagala R, Jeyabalan J, et al. Exosomes for the enhanced tissue bioavailability and efficacy of curcumin. The AAPS Journal, 2017, 19(6): 1691-1702. doi: 10.1208/s12248-017-0154-9
[155]	Li D, Yao S R, Zhou Z F, et al. Hyaluronan decoration of milk exosomes directs tumor-specific delivery of doxorubicin. Carbohydrate Research, 2020, 493: 108032. doi: 10.1016/j.carres.2020.108032
[156]	Luo S Q, Sun X L, Huang M, et al. Enhanced neuroprotective effects of epicatechin gallate encapsulated by bovine milk-derived exosomes against parkinson’s disease through antiapoptosis and antimitophagy. Journal of Agricultural and Food Chemistry, 2021, 69(17): 5134-5143. doi: 10.1021/acs.jafc.0c07658
[157]	Tao H Y, Xu H L, Zuo L, et al. Exosomes-coated bcl-2 siRNA inhibits the growth of digestive system tumors both in vitro and in vivo. International Journal of Biological Macromolecules, 2020, 161: 470-480. doi: 10.1016/j.ijbiomac.2020.06.052
[158]	Shandilya S, Rani P, Onteru S K, et al. Natural ligand-receptor mediated loading of siRNA in milk derived exosomes. Journal of Biotechnology, 2020, 318: 1-9. doi: S0168-1656(20)30103-6 pmid: 32361020
[159]	Grossen P, Portmann M, Koller E, et al. Evaluation of bovine milk extracellular vesicles for the delivery of locked nucleic acid antisense oligonucleotides. European Journal of Pharmaceutics and Biopharmaceutics, 2021, 158: 198-210. doi: 10.1016/j.ejpb.2020.11.012 pmid: 33248268

[1]	吕慧中,赵晨辰,朱链,许娜. 外泌体靶向递药在肿瘤治疗中的进展[J]. 中国生物工程杂志, 2021, 41(5): 79-86.
[2]	王伟东,杜加茹,张运尚,樊剑鸣. CRISPR/Cas9在人病毒感染相关疾病治疗研究中的应用^*[J]. 中国生物工程杂志, 2020, 40(12): 18-24.
[3]	杨春艳,王磊,穆登彩,李芳芳,沈昊,郑尚永. 基因编辑技术在疾病治疗中的研究进展 ^*[J]. 中国生物工程杂志, 2019, 39(11): 87-95.
[4]	夏小燕, 傅仲华. 生物大分子分离纯化技术的重大突破──灌注层析系统[J]. 中国生物工程杂志, 1994, 14(5): 40-45.
[5]	吴凯瑾. 单克隆携带治疗药物趋向体靶[J]. 中国生物工程杂志, 1983, 3(4): 63-64.

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