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Macrophages are important members of the innate immune system that can be reversibly polarized by different microenvironment signals. Exosomes secreted from cells are lipid bilayer membrane vesicles carrying versatile biomolecules, which displays unique properties and biological functions. Recent studies have shown that macrophage derived exosomes as an extracellular vehicle can deliver diverse cargoes including small molecules, nanoparticles, and biological macromolecules to recipient cells, and thus affect the progression of cancers and other diseases. Moreover, exosomes secreted by different phenotypes of macrophages provide different therapeutic options. Thus, in this review, we summarized recent progress in the macrophage derived exosomes as carriers for delivering different types of cargos. Then the engineering principles and their applications are elaborated. In the end, challenges and prospects of macrophage derived exosomes for drug delivery and disease treatment are also discussed.

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Recent advances in macrophage-derived exosomes as delivery vehicles

Show Author's information Shumin Wang1,2,§Yajie Yang1,3,§Shenhua Li3Haibo Chen1Yongsheng Zhao1( )Jing Mu1,2( )
Department of Nuclear Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China
Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, 518036, China
Central Laboratory, Peking University Shenzhen Hospital, Shenzhen 518036, China

§ Shumin Wang and Yajie Yang contributed equally to this work.


Macrophages are important members of the innate immune system that can be reversibly polarized by different microenvironment signals. Exosomes secreted from cells are lipid bilayer membrane vesicles carrying versatile biomolecules, which displays unique properties and biological functions. Recent studies have shown that macrophage derived exosomes as an extracellular vehicle can deliver diverse cargoes including small molecules, nanoparticles, and biological macromolecules to recipient cells, and thus affect the progression of cancers and other diseases. Moreover, exosomes secreted by different phenotypes of macrophages provide different therapeutic options. Thus, in this review, we summarized recent progress in the macrophage derived exosomes as carriers for delivering different types of cargos. Then the engineering principles and their applications are elaborated. In the end, challenges and prospects of macrophage derived exosomes for drug delivery and disease treatment are also discussed.

Keywords: inflammation, drug delivery, cancer, macrophage polarization, macrophage-derived exosomes



Neupane, K. R.; McCorkle, J. R.; Kopper, T. J.; Lakes, J. E.; Aryal, S. P.; Abdullah, M.; Snell, A. A.; Gensel, J. C.; Kolesar, J.; Richards, C. I. Macrophage-engineered vesicles for therapeutic delivery and bidirectional reprogramming of immune cell polarization. ACS Omega 2021, 6, 3847–3857.


Sica, A.; Erreni, M.; Allavena, P.; Porta, C. Macrophage polarization in pathology. Cell. Mol. Life Sci. 2015, 72, 4111–4126.


Bart, V. M. T.; Pickering, R. J.; Taylor, P. R.; Ipseiz, N. Macrophage reprogramming for therapy. Immunology 2021, 163, 128–144.


Cassetta, L.; Pollard, J. W. Targeting macrophages: Therapeutic approaches in cancer. Nat. Rev. Drug Discov. 2018, 17, 887–904.


Martinez, F. O.; Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014, 6, 13.


Sica, A.; Mantovani, A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Invest. 2012, 122, 787–795.


Mantovani, A.; Marchesi, F.; Malesci, A.; Laghi, L.; Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017, 14, 399–416.


Mantovani, A.; Biswas, S. K.; Galdiero, M. R.; Sica, A.; Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 2013, 229, 176–185.


Biswas, S. K.; Allavena, P.; Mantovani, A. Tumor-associated macrophages: Functional diversity, clinical significance, and open questions. Semin. Immunopathol. 2013, 35, 585–600.


Jeppesen, D. K.; Fenix, A. M.; Franklin, J. L.; Higginbotham, J. N.; Zhang, Q.; Zimmerman, L. J.; Liebler, D. C.; Ping, J.; Liu, Q.; Evans, R. et al. Reassessment of exosome composition. Cell 2019, 177, 428–445. e18.


Théry, C.; Witwer, K. W.; Aikawa, E.; Alcaraz, M. J.; Anderson, J. D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G. K. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 2018, 7, 1535750.


Purushothaman, A.; Bandari, S. K.; Liu, J.; Mobley, J. A.; Brown, E. E.; Sanderson, R. D. Fibronectin on the surface of myeloma cell-derived exosomes mediates exosome-cell interactions. J. Biol. Chem. 2016, 291, 1652–1663.


Mulcahy, L. A.; Pink, R. C.; Carter, D. R. F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 2014, 3, 24641.


Gutiérrez-Vázquez, C.; Villarroya-Beltri, C.; Mittelbrunn, M.; Sánchez-Madrid, F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol. Rev. 2013, 251, 125–142.


Haney, M. J.; Klyachko, N. L.; Zhao, Y. L.; Gupta, R.; Plotnikova, E. G.; He, Z. J.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A. V. et al. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J. Control. Release 2015, 207, 18–30.


Whiteside, T. L. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem. Soc. Trans. 2013, 41, 245–251.


Wang, X.; He, L.; Huang, X. B.; Zhang, S. S.; Cai, W. J.; Che, F. F.; Zhu, Y. Z.; Dai, J. Y. Recent progress of exosomes in multiple myeloma: Pathogenesis, diagnosis, prognosis and therapeutic strategies. Cancers (Basel) 2021, 13, 1635.


Zhou, B. T.; Xu, K. L.; Zheng, X.; Chen, T.; Wang, J.; Song, Y. M.; Shao, Y. K.; Zheng, S. Application of exosomes as liquid biopsy in clinical diagnosis. Signal Transduct. Target. Ther. 2020, 5, 144.


Yu, D.; Li, Y. X.; Wang, M. Y.; Gu, J. M.; Xu, W. R.; Cai, H.; Fang, X. J.; Zhang, X. Exosomes as a new frontier of cancer liquid biopsy. Mol. Cancer 2022, 21, 56.


Dai, H. X.; Fan, Q.; Wang, C. Recent applications of immunomodulatory biomaterials for disease immunotherapy. Exploration 2022, 2, 20210157.


Meng, W. R.; He, C. S.; Hao, Y. Y.; Wang, L. L.; Li, L.; Zhu, G. Q. Prospects and challenges of extracellular vesicle-based drug delivery system: Considering cell source. Drug Deliv. 2020, 27, 585–598.


Murray, P. J.; Allen, J.; Biswas, S.; Fisher, E.; Gilroy, D.; Goerdt, S.; Gordon, S.; Hamilton, J.; Ivashkiv, L.; Lawrence, T. et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 2014, 41, 14–20.


Zhou, Q. J.; Fang, T. T.; Wei, S. Y.; Chai, S. Q.; Yang, H. F.; Tai, M. C.; Cai, Y. Macrophages in melanoma: A double-edged sword and targeted therapy strategies (Review). Exp. Ther. Med. 2022, 24, 640.


Luo, S. H.; Yang, G. H.; Ye, P.; Cao, N. Q.; Chi, X. X.; Yang, W. H.; Yan, X. W. Macrophages are a double-edged sword: Molecular crosstalk between tumor-associated macrophages and cancer stem cells. Biomolecules 2022, 12, 850.


Ivashkiv, L. B. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 2013, 34, 216–223.


Hamers, A. A. J.; Pillai, A. B. A sweet alternative: Maintaining M2 macrophage polarization. Sci. Immunol. 2018, 3, eaav7759.


Martinez, F. O.; Helming, L.; Gordon, S. Alternative activation of macrophages: An immunologic functional perspective. Annu. Rev. Immunol. 2009, 27, 451–483.


Xuan, W. J.; Qu, Q.; Zheng, B.; Xiong, S. D.; Fan, G. H. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines. J. Leukoc. Biol. 2015, 97, 61–69.


Zhou, D. X.; Huang, C.; Lin, Z.; Zhan, S. X.; Kong, L. N.; Fang, C. B.; Li, J. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell. Signal. 2014, 26, 192–197.


Shan, X. X.; Zhang, C. Y.; Mai, C.; Hu, X. R.; Cheng, N.; Chen, W. D.; Peng, D. Y.; Wang, L.; Ji, Z. J.; Xie, Y. The biogenesis, biological functions, and applications of macrophage-derived exosomes. Front. Mol. Biosci. 2021, 8, 715461.


Choo, Y. W.; Kang, M.; Kim, H. Y.; Han, J.; Kang, S.; Lee, J. R.; Jeong, G. J.; Kwon, S. P.; Song, S. Y.; Go, S. et al. M1 macrophage-derived nanovesicles potentiate the anticancer efficacy of immune checkpoint inhibitors. ACS Nano 2018, 12, 8977–8993.


Niu, C. G.; Wang, X.; Zhao, M. M.; Cai, T. X.; Liu, P. B.; Li, J. Z.; Willard, B.; Zu, L. Y.; Zhou, E. C.; Li, Y. F. et al. Macrophage foam cell-derived extracellular vesicles promote vascular smooth muscle cell migration and adhesion. J. Am. Heart Assoc. 2016, 5, e004099.


Kim, H.; Wang, S. Y.; Kwak, G.; Yang, Y.; Kwon, I. C.; Kim, S. H. Exosome-guided phenotypic switch of M1 to M2 macrophages for cutaneous wound healing. Adv. Sci. (Weinh. ) 2019, 6, 1900513.


Yao, M. Y.; Zhang, W. H.; Ma, W. T.; Liu, Q. H.; Xing, L. H.; Zhao, G. F. microRNA-328 in exosomes derived from M2 macrophages exerts a promotive effect on the progression of pulmonary fibrosis via FAM13A in a rat model. Exp. Mol. Med. 2019, 51, 1–16.


Chen, J. L.; Zhou, R. P.; Liang, Y. M.; Fu, X. J.; Wang, D. R.; Wang, C. Blockade of lncRNA-ASLNCS5088-enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 2019, 33, 12200–12212.


Dai, Y. X.; Wang, S.; Chang, S. F.; Ren, D. Y.; Shali, S.; Li, C. G.; Yang, H. B.; Huang, Z. Y.; Ge, J. B. M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. J. Mol. Cell. Cardiol. 2020, 142, 65–79.


Tauro, B. J.; Greening, D. W.; Mathias, R. A.; Ji, H.; Mathivanan, S.; Scott, A. M.; Simpson, R. J. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods 2012, 56, 293–304.


Kamerkar, S.; Lebleu, V. S.; Sugimoto, H.; Yang, S. J.; Ruivo, C. F.; Melo, S. A.; Lee, J. J.; Kalluri, R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017, 546, 498–503.


Cheruvanky, A.; Zhou, H.; Pisitkun, T.; Kopp, J. B.; Knepper, M. A.; Yuen, P. S. T.; Star, R. A. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am. J. Physiol. Renal Physiol. 2007, 292, F1657–F1661.


Clancy, J. W.; Sedgwick, A.; Rosse, C.; Muralidharan-Chari, V.; Raposo, G.; Method, M.; Chavrier, P.; D'souza-Schorey, C. Regulated delivery of molecular cargo to invasive tumour-derived microvesicles. Nat. Commun. 2015, 6, 6919.


Wu, K. R.; Xing, F.; Wu, S. Y.; Watabe, K. Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside. Biochim. Biophys. Acta (BBA)-Rev. Cancer 2017, 1868, 538–563.


Prada, I.; Meldolesi, J. Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets. Int. J. Mol. Sci. 2016, 17, 1296.


El Andaloussi, S.; Lakhal, S.; Mäger, I.; Wood, M. J. A. Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 2013, 65, 391–397.


Das, C. K.; Jena, B. C.; Banerjee, I.; Das, S.; Parekh, A.; Bhutia, S. K.; Mandal, M. Exosome as a novel shuttle for delivery of therapeutics across biological barriers. Mol. Pharm. 2019, 16, 24–40.


Zhu, L.; Sun, H. T.; Wang, S.; Huang, S. L.; Zheng, Y.; Wang, C. Q.; Hu, B. Y.; Qin, W.; Zou, T. T.; Fu, Y. et al. Isolation and characterization of exosomes for cancer research. J. Hematol. Oncol. 2020, 13, 152.


Vader, P.; Mol, E. A.; Pasterkamp, G.; Schiffelers, R. M. Extracellular vesicles for drug delivery. Adv. Drug Deliv. Rev. 2016, 106, 148–156.


Kim, H.; Jang, H.; Cho, H.; Choi, J.; Hwang, K. Y.; Choi, Y.; Kim, S. H.; Yang, Y. Recent advances in exosome-based drug delivery for cancer therapy. Cancers (Basel) 2021, 13, 4435.


Liu, J. J.; Wu, F. L.; Zhou, H. M. Macrophage-derived exosomes in cancers: Biogenesis, functions and therapeutic applications. Immunol. Lett. 2020, 227, 102–108.


Wu, T. T.; Liu, Y.; Cao, Y.; Liu, Z. H. Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma. Adv. Mater. 2022, 34, 2110364.


Wu, G. H.; Zhang, J. F.; Zhao, Q. R.; Zhuang, W. R.; Ding, J. J.; Zhang, C.; Gao, H. J.; Pang, D. W.; Pu, K. Y.; Xie, H. Y. Molecularly engineered macrophage-derived exosomes with inflammation tropism and intrinsic heme biosynthesis for atherosclerosis treatment. Angew. Chem., Int. Ed. 2020, 59, 4068–4074.


Gong, C. N.; Tian, J.; Wang, Z.; Gao, Y.; Wu, X.; Ding, X. Y.; Qiang, L.; Li, G. R.; Han, Z. M.; Yuan, Y. F. et al. Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy. J. Nanobiotechnol. 2019, 17, 93.


Rayamajhi, S.; Nguyen, T. D. T.; Marasini, R.; Aryal, S. Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery. Acta Biomater. 2019, 94, 482–494.


Wang, Y. D.; Jia, L. L.; Xie, Y.; Cai, Z. J.; Liu, Z. J.; Shen, J.; Lu, Y.; Wang, Y. P.; Su, S. G.; Ma, Y. K. et al. Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development. Atherosclerosis 2019, 289, 64–72.


Kim, M. S.; Haney, M. J.; Zhao, Y. L.; Mahajan, V.; Deygen, I.; Klyachko, N. L.; Inskoe, E.; Piroyan, A.; Sokolsky, M.; Okolie, O. et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 2016, 12, 655–664.


Haney, M. J.; Zhao, Y. L.; Jin, Y. S.; Li, S. M.; Bago, J. R.; Klyachko, N. L.; Kabanov, A. V.; Batrakova, E. V. Macrophage-derived extracellular vesicles as drug delivery systems for triple negative breast cancer (TNBC) therapy. J. Neuroimmune Pharmacol. 2020, 15, 487–500.


Xia, Y. Q.; Rao, L.; Yao, H. M.; Wang, Z. L.; Ning, P. B.; Chen, X. Y. Engineering macrophages for cancer immunotherapy and drug delivery. Adv. Mater. 2020, 32, 2002054.


Lee, H.; Park, H.; Noh, G. J.; Lee, E. S. pH-responsive hyaluronate-anchored extracellular vesicles to promote tumor-targeted drug delivery. Carbohydr. Polym. 2018, 202, 323–333.


Jia, G.; Han, Y.; An, Y. L.; Ding, Y. N.; He, C.; Wang, X. H.; Tang, Q. S. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials 2018, 178, 302–316.


Rayamajhi, S.; Marasini, R.; Nguyen, T. D. T.; Plattner, B. L.; Biller, D.; Aryal, S. Strategic reconstruction of macrophage-derived extracellular vesicles as a magnetic resonance imaging contrast agent. Biomater. Sci. 2020, 8, 2887–2904.


Hwang, D. W.; Choi, H.; Jang, S. C.; Yoo, M. Y.; Park, J. Y.; Choi, N. E.; Oh, H. J.; Ha, S.; Lee, Y. S.; Jeong, J. M. et al. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99mTc-HMPAO. Sci. Rep. 2015, 5, 15636.


Li, S.; Wu, Y. J.; Ding, F.; Yang, J. P.; Li, J.; Gao, X. H.; Zhang, C.; Feng, J. Engineering macrophage-derived exosomes for targeted chemotherapy of triple-negative breast cancer. Nanoscale 2020, 12, 10854–10862.


Zhang, X. H.; Detering, L.; Sultan, D.; Luehmann, H.; Li, L.; Heo, G. S.; Zhang, X. L.; Lou, L. L.; Grierson, P. M.; Greco, S. et al. CC chemokine receptor 2-targeting copper nanoparticles for positron emission tomography-guided delivery of gemcitabine for pancreatic ductal adenocarcinoma. ACS Nano 2021, 15, 1186–1198.


Lee, H.; Park, H.; Yu, H. S.; Na, K.; Oh, K. T.; Lee, E. S. Dendritic cell-targeted pH-responsive extracellular vesicles for anticancer vaccination. Pharmaceutics 2019, 11, 54.


Yuan, D. F.; Zhao, Y. L.; Banks, W. A.; Bullock, K. M.; Haney, M.; Batrakova, E.; Kabanov, A. V. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 2017, 142, 1–12.


Gunassekaran, G. R.; Poongkavithai Vadevoo, S. M.; Baek, M. C.; Lee, B. M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages. Biomaterials 2021, 278, 121137.


Ma, X. T.; Yao, M. N.; Gao, Y.; Yue, Y.; Li, Y.; Zhang, T. J.; Nie, G. J.; Zhao, X.; Liang, X. L. Functional immune cell-derived exosomes engineered for the trilogy of radiotherapy sensitization. Adv. Sci. (Weinh. ) 2022, 9, e2106031.


El Andaloussi, S.; Mäger, I.; Breakefield, X. O.; Wood, M. J. A. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013, 12, 347–357.


Zhao, Y. M.; Zheng, Y. L.; Zhu, Y.; Zhang, Y.; Zhu, H. Y.; Liu, T. Q. M1 macrophage-derived exosomes loaded with gemcitabine and deferasirox against chemoresistant pancreatic cancer. Pharmaceutics 2021, 13, 1493.


Sun, D. M.; Zhuang, X. Y.; Xiang, X. Y.; Liu, Y. L.; Zhang, S. Y.; Liu, C. R.; Barnes, S.; Grizzle, W.; Miller, D.; Zhang, H. G. A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 2010, 18, 1606–1614.


Kawikova, I.; Askenase, P. W. Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res. 2015, 1617, 63–71.


Li, X. M.; Tsibouklis, J.; Weng, T. T.; Zhang, B. N.; Yin, G. Q.; Feng, G. Z.; Cui, Y. D.; Savina, I. N.; Mikhalovska, L. I.; Sandeman, S. R. et al. Nano carriers for drug transport across the blood–brain barrier. J. Drug Target. 2017, 25, 17–28.


Shan, S. B.; Cheng, J. G.; Sun, Y.; Wang, Y. C.; Xia, B. Z.; Tan, H.; Pan, C. C.; Gu, G. C.; Zhong, J.; Qing, G. C. et al. Functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for diffuse intrinsic pontine gliomas therapy. Adv. Sci. (Weinh. ) 2022, 9, e2200353.


Riederer, P.; Sofic, E.; Rausch, W. D.; Schmidt, B.; Reynolds, G. P.; Jellinger, K.; Youdim, M. B. H. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 1989, 52, 515–520.


Abraham, S.; Soundararajan, C. C.; Vivekanandhan, S.; Behari, M. Erythrocyte antioxidant enzymes in Parkinson's disease. Indian J. Med. Res. 2005, 121, 111–115.


Jang, S. C.; Kim, O. Y.; Yoon, C. M.; Choi, D. S.; Roh, T. Y.; Park, J.; Nilsson, J.; Lötvall, J.; Kim, Y. K.; Gho, Y. S. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 2013, 7, 7698–7710.


Muller, W. A. Getting leukocytes to the site of inflammation. Vet. Pathol. 2013, 50, 7–22.


Hao, S. G.; Bai, O.; Li, F.; Yuan, J. Y.; Laferte, S.; Xiang J. Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumour immunity. Immunology 2007, 120, 90–102.


Riley, R. S.; June, C. H.; Langer, R.; Mitchell, M. J. Delivery technologies for cancer immunotherapy. Nat. Rev. Drug Discov. 2019, 18, 175–196.


Duan, X. P.; Chan, C.; Lin, W. B. Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew. Chem., Int. Ed. 2019, 58, 670–680.


Jiang, J. P.; Mei, J.; Ma, Y. F.; Jiang, S. S.; Zhang, J.; Yi, S. Q.; Feng, C. J.; Liu, Y.; Liu, Y. Tumor hijacks macrophages and microbiota through extracellular vesicles. Exploration 2022, 2, 20210144.


DeNardo, D. G.; Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 2019, 19, 369–382.


Mosser, D. M.; Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969.


Cheng, L. F.; Wang, Y. H.; Huang, L. Exosomes from M1-Polarized Macrophages Potentiate the Cancer Vaccine by Creating a Pro-inflammatory Microenvironment in the Lymph Node. Mol. Ther. 2017, 25, 1665–1675.


Wang, P. P.; Wang, H. H.; Huang, Q. Q.; Peng, C.; Yao, L.; Chen, H.; Qiu, Z.; Wu, Y. F.; Wang, L.; Chen, W. D. Exosomes from M1-polarized macrophages enhance paclitaxel antitumor activity by activating macrophages-mediated inflammation. Theranostics 2019, 9, 1714–1727.


Su, M. J.; Aldawsari, H.; Amiji, M. Pancreatic cancer cell exosome-mediated macrophage reprogramming and the role of microRNAs 155 and 125b2 transfection using nanoparticle delivery systems. Sci. Rep. 2016, 6, 30110.


Saccani, A.; Schioppa, T.; Porta, C.; Biswas, S. K.; Nebuloni, M.; Vago, L.; Bottazzi, B.; Colombo, M. P.; Mantovani, A.; Sica, A. p50 nuclear factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006, 66, 11432–11440.


Squadrito, M. L.; Pucci, F.; Magri, L.; Moi, D.; Gilfillan, G. D.; Ranghetti, A.; Casazza, A.; Mazzone, M.; Lyle, R.; Naldini, L. et al. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep. 2012, 1, 141–154.


Squadrito, M. L.; Etzrodt, M.; De Palma, M.; Pittet, M. J. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol. 2013, 34, 350–359.


Guo, C. K.; Ouyang, Y. M.; Cai, J.; Xiong, L.; Chen, Y. J.; Zeng, X. L.; Liu, A. W. High expression of IL-4R enhances proliferation and invasion of hepatocellular carcinoma cells. Int. J. Biol. Markers 2017, 32, e384–e390.


Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J. J.; Lötvall, J. O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659.


Mashouri, L.; Yousefi, H.; Aref, A. R.; Ahadi, A. M.; Molaei, F.; Alahari, S. K. Exosomes: Composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol. Cancer 2019, 18, 75.


Chin, A. R.; Fong, M. Y.; Somlo, G.; Wu, J.; Swiderski, P.; Wu, X. W.; Wang, S. E. Cross-kingdom inhibition of breast cancer growth by plant miR159. Cell Res. 2016, 26, 217–228.


Moris, D.; Beal, E. W.; Chakedis, J.; Burkhart, R. A.; Schmidt, C.; Dillhoff, M.; Zhang, X. F.; Theocharis, S.; Pawlik, T. M. Role of exosomes in treatment of hepatocellular carcinoma. Surg. Oncol. 2017, 26, 219–228.


Li, X.; Li, C. Y.; Zhang, L. P.; Wu, M.; Cao, K.; Jiang, F. F.; Chen, D. X.; Li, N.; Li, W. H. The significance of exosomes in the development and treatment of hepatocellular carcinoma. Mol. Cancer 2020, 19, 1.


Gilligan, K. E.; Dwyer, R. M. Engineering exosomes for cancer therapy. Int. J. Mol. Sci. 2017, 18, 1122.


Tofaris, G. K. A critical assessment of exosomes in the pathogenesis and stratification of Parkinson's disease. J. Parkinsons Dis. 2017, 7, 569–576.


Ha, D.; Yang, N. N.; Nadithe, V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: Current perspectives and future challenges. Acta Pharm. Sin. B 2016, 6, 287–296.


Sun, Z. W.; Jiang, Y. Y.; Stenzel, M. Manipulating endogenous exosome biodistribution for therapy. SmartMat 2021, 2, 127–130.


El-Andaloussi, S.; Lee, Y.; Lakhal-Littleton, S.; Li, J. H.; Seow, Y.; Gardiner, C.; Alvarez-Erviti, L.; Sargent, I. L.; Wood, M. J. A. Exosome-mediated delivery of siRNA in vitro and in vivo. Nat. Protoc. 2012, 7, 2112–2126.


Wiklander, O. P. B.; Nordin, J. Z.; O'loughlin, A.; Gustafsson, Y.; Corso, G.; Mäger, I.; Vader, P.; Lee, Y.; Sork, H.; Seow, Y. et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 2015, 4, 26316.


Barile, L.; Vassalli, G. Exosomes: Therapy delivery tools and biomarkers of diseases. Pharmacol. Ther. 2017, 174, 63–78.


Palazzolo, S.; Bayda, S.; Hadla, M.; Caligiuri, I.; Corona, G.; Toffoli, G.; Rizzolio, F. The clinical translation of organic nanomaterials for cancer therapy: A focus on polymeric nanoparticles, micelles, liposomes and exosomes. Curr. Med. Chem. 2018, 25, 4224–4268.


Tominaga, N.; Kosaka, N.; Ono, M.; Katsuda, T.; Yoshioka, Y.; Tamura, K.; Lötvall, J.; Nakagama, H.; Ochiya, T. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nat. Commun. 2015, 6, 6716.


Sieow, B. F. L.; Wun, K. S.; Yong, W. P.; Hwang, I. Y.; Chang, M. W. Tweak to treat: Reprograming bacteria for cancer treatment. Trends Cancer 2021, 7, 447–464.


Kalluri, R.; LeBleu, V. S. The biology, function, and biomedical applications of exosomes. Science 2020, 367, eaau6977.


Ingato, D.; Lee, J. U.; Sim, S. J.; Kwon, Y. J. Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery. J. Control. Release 2016, 241, 174–185.


Rak, J.; Guha, A. Extracellular vesicles-vehicles that spread cancer genes. Bioessays 2012, 34, 489–497.


Polakovicova, I.; Jerez, S.; Wichmann, I. A.; Sandoval-Bórquez, A.; Carrasco-Véliz, N.; Corvalán, A. H. Role of microRNAs and exosomes in Helicobacter pylori and Epstein-Barr virus associated gastric cancers. Front. Microbiol. 2018, 9, 636.

Vella, L. J.; Coleman, B.; Hill, A. F. Generation of infectious prions and detection with the prion-infected cell assay. In Prions. Lawson, V. A., Ed.; Humana Press: New York, 2017; pp 105–118.

Webber, J.; Clayton, A. How pure are your vesicles? J. Extracell. Vesicles 2013, 2, 19861.


Corso, G.; Mäger, I.; Lee, Y.; Görgens, A.; Bultema, J.; Giebel, B.; Wood, M. J. A.; Nordin, J. Z.; Andaloussi, S. E. Reproducible and scalable purification of extracellular vesicles using combined bind-elute and size exclusion chromatography. Sci. Rep. 2017, 7, 11561.


Aung, T.; Chapuy, B.; Vogel, D.; Wenzel, D.; Oppermann, M.; Lahmann, M.; Weinhage, T.; Menck, K.; Hupfeld, T.; Koch, R. et al. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc. Natl. Acad. Sci. USA 2011, 108, 15336–15341.


Lösche, W.; Scholz, T.; Temmler, U.; Oberle, V.; Claus, R. A. Platelet-derived microvesicles transfer tissue factor to monocytes but not to neutrophils. Platelets 2004, 15, 109–115.

Publication history
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Publication history

Received: 19 October 2022
Revised: 07 December 2022
Accepted: 28 December 2022
Published: 31 December 2022
Issue date: December 2022


© The Author(s) 2022. Nano TransMed published by Tsinghua University Press.



This work was supported by Natural Science Foundation of China (No. 32101074) and China Scientific Research Foundation of Peking University Shenzhen Hospital (No. KYQD202100X).

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