Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization
Abstract
:1. Introduction
2. Cargo Loading Methods
2.1. Pre-Loading Method
2.1.1. Co-Incubation
2.1.2. Genetic Modification
2.2. Post-loading
2.2.1. Active Loading
2.2.2. Passive Loading
3. Improve Tumor-Targeting Potential of Exosomes
3.1. Genetic Modification
3.2. Chemical Modification
4. Future Outlooks
- Exosomes are nanovesicles with a diameter size between 30 and 150 nm, originating from inside cells with different biological cargo.
- Exosomes are present in most body fluids and therefore can travel to different organs throughout the body.
- Exosome entity from different cells is highly variable regarding their function and cargo.
- Exosomes can encapsulate various exogenous therapeutic cargo and deliver them to target cells.
- The exosomal surface can be engineered for imaging, targeting, and therapy objects.
- What are/is the common way/s for isolation and purification of exosomes? Exosomes are heterogeneous both in size and function, and different methods are used to isolate and purify exosomes from various sources such as cell culture medium or body fluids. Therefore, a gold-standard method is needed.
- Which source cells are suitable for the massive production of exosomes? The most important issue is large-scale good manufacturing practice (GMP)−exosome production under GMP-compliant procedures to safeguard quality, safety, and reliability. Therefore, safe and confident parental cells must be selected for exosomes yield.
- What are/is the standard/s method/s for loading exosomes with exogenous cargo?
- Which surface modification approach/es is/are most common for the improving exosomes targeting abilities? Mainly two methods, namely genetic and chemical modification approaches, are used to functionalize the surface of exosomes for increasing the tumor-targeting ability of exosomes. Exosomal surfaces are decorated with various biomolecules with a certain function. This may make it difficult for selecting a suitable and safe target residual on the surface of the exosomes.
- Do surface modification methods damage exosome structure and function? Surface modification (functionalization), especially chemical ones, may blind or harm available residuals on exosome surface. Therefore, this may affect exosomes’ pharmacokinetics and biodistribution in the body.
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA A Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef]
- Cantini, L.; Mentrasti, G.; Russo, G.L.; Signorelli, D.; Pasello, G.; Rijavec, E.; Russano, M.; Antonuzzo, L.; Rocco, D.; Giusti, R.; et al. Evaluation of COVID-19 impact on DELAYing diagnostic-therapeutic pathways of lung cancer patients in Italy (COVID-DELAY study): Fewer cases and higher stages from a real-world scenario. ESMO Open 2022, 7, 100406. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.P.; Zheng, C.C.; Huang, Y.N.; He, M.L.; Xu, W.W.; Li, B. Molecular mechanisms of chemo-and radiotherapy resistance and the potential implications for cancer treatment. Med. Comm. 2021, 2, 315–340. [Google Scholar] [CrossRef] [PubMed]
- Bao, Y.; Liu, S.; Zhou, Q.; Cai, P.; Anfossi, S.; Li, Q.; Hu, Y.; Liu, M.; Fu, J.; Rong, T. Three-dimensional conformal radiotherapy with concurrent chemotherapy for postoperative recurrence of esophageal squamous cell carcinoma: Clinical efficacy and failure pattern. Radiat. Oncol. 2013, 8, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yagawa, Y.; Tanigawa, K.; Kobayashi, Y.; Yamamoto, M. Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery. J. Cancer Metastasis Treat. 2017, 3, 218–230. [Google Scholar] [CrossRef]
- Bach, P.B.; Jett, J.R.; Pastorino, U.; Tockman, M.S.; Swensen, S.J.; Begg, C.B. Computed tomography screening and lung cancer outcomes. JAMA 2007, 297, 953–961. [Google Scholar] [CrossRef] [Green Version]
- Zusman, I.; Zimber, A.; Nyska, A. Role of morphological methods in the analysis of chemically induced colon cancer in rats. Cells Tissues Organs 1991, 142, 351–356. [Google Scholar] [CrossRef]
- Gomes-da-Silva, L.C.; Fonseca, N.A.; Moura, V.; Pedroso de Lima, M.C.; Simões, S.; Moreira, J.N. Lipid-based nanoparticles for siRNA delivery in cancer therapy: Paradigms and challenges. Acc. Chem. Res. 2012, 45, 1163–1171. [Google Scholar] [CrossRef]
- Edis, Z.; Wang, J.; Waqas, M.K.; Ijaz, M.; Ijaz, M. Nanocarriers-mediated drug delivery systems for anticancer agents: An overview and perspectives. Int. J. Nanomed. 2021, 16, 1313. [Google Scholar] [CrossRef]
- Ramanathan, S.; Gopinath, S.C.B.; Arshad, M.K.M.; Poopalan, P.; Perumal, V. 2-Nanoparticle Synthetic Methods: Strength and Limitations. In Nanoparticles in Analytical and Medical Devices; Gopinath, S.C.B., Gang, F., Eds.; Elsevier: Amsterdam, The Netherlands, 2021; pp. 31–43. [Google Scholar] [CrossRef]
- van der Meel, R.; Sulheim, E.; Shi, Y.; Kiessling, F.; Mulder, W.J.; Lammers, T. Smart cancer nanomedicine. Nat. Nanotechnol. 2019, 14, 1007–1017. [Google Scholar] [CrossRef]
- Elsharkasy, O.M.; Nordin, J.Z.; Hagey, D.W.; de Jong, O.G.; Schiffelers, R.M.; Andaloussi, S.E.; Vader, P. Extracellular vesicles as drug delivery systems: Why and how? Adv. Drug Deliv. Rev. 2020, 159, 332–343. [Google Scholar] [CrossRef] [PubMed]
- Rahbarghazi, R.; Jabbari, N.; Sani, N.A.; Asghari, R.; Salimi, L.; Kalashani, S.A.; Feghhi, M.; Etemadi, T.; Akbariazar, E.; Mahmoudi, M.; et al. Tumor-derived extracellular vesicles: Reliable tools for Cancer diagnosis and clinical applications. Cell Commun. Signal. 2019, 17, 73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rezaie, J.; Ahmadi, M.; Ravanbakhsh, R.; Mojarad, B.; Mahbubfam, S.; Shaban, S.A.; Shadi, K.; Berenjabad, N.J.; Etemadi, T. Tumor-derived extracellular vesicles: The metastatic organotropism drivers. Life Sci. 2021, 120216. [Google Scholar] [CrossRef]
- Shaban, S.A.; Rezaie, J.; Nejati, V. Exosomes Derived from Senescent Endothelial Cells Contain Distinct Pro-angiogenic miRNAs and Proteins. Cardiovasc. Toxicol. 2022, 22, 592–601. [Google Scholar] [CrossRef] [PubMed]
- Brennan, K.; Martin, K.; FitzGerald, S.P.; O’Sullivan, J.; Wu, Y.; Blanco, A.; Richardson, C.; Mc Gee, M.M. A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Sci. Rep. 2020, 10, 1039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Doyle, L.M.; Wang, M.Z. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hassanpour, M.; Rezaie, J.; Darabi, M.; Hiradfar, A.; Rahbarghazi, R.; Nouri, M. Autophagy modulation altered differentiation capacity of CD146+ cells toward endothelial cells, pericytes, and cardiomyocytes. Stem Cell Res. Ther. 2020, 11, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Feghhi, M.; Rezaie, J.; Akbari, A.; Jabbari, N.; Jafari, H.; Seidi, F.; Szafert, S. Effect of multi-functional polyhydroxylated polyhedral oligomeric silsesquioxane (POSS) nanoparticles on the angiogenesis and exosome biogenesis in human umbilical vein endothelial cells (HUVECs). Mater. Des. 2021, 197, 109227. [Google Scholar] [CrossRef]
- Soraya, H.; Sani, N.A.; Jabbari, N.; Rezaie, J. Metformin increases exosome biogenesis and secretion in U87 MG human glioblastoma cells: A possible mechanism of therapeutic resistance. Arch. Med. Res. 2021, 52, 151–162. [Google Scholar] [CrossRef]
- Kou, X.; Xu, X.; Chen, C.; Sanmillan, M.L.; Cai, T.; Zhou, Y.; Giraudo, C.; Le, A.; Shi, S. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci. Transl. Med. 2018, 10, eaai8524. [Google Scholar] [CrossRef] [Green Version]
- Tricarico, C.; Clancy, J.; D’Souza-Schorey, C. Biology and biogenesis of shed microvesicles. Small GTPases 2017, 8, 220–232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar] [CrossRef] [PubMed]
- Patil, S.M.; Sawant, S.S.; Kunda, N.K. Exosomes as drug delivery systems: A brief overview and progress update. Eur. J. Pharm. Biopharm. 2020, 154, 259–269. [Google Scholar] [CrossRef] [PubMed]
- Kreimer, S.; Belov, A.M.; Ghiran, I.; Murthy, S.K.; Frank, D.A.; Ivanov, A.R. Mass-spectrometry-based molecular characterization of extracellular vesicles: Lipidomics and proteomics. J. Proteome Res. 2015, 14, 2367–2384. [Google Scholar] [CrossRef] [PubMed]
- Van Deun, J.; Mestdagh, P.; Agostinis, P.; Akay, Ö.; Anand, S.; Anckaert, J.; Martinez, Z.A.; Baetens, T.; Beghein, E.; Bertier, L. EV-TRACK: Transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods 2017, 14, 228–232. [Google Scholar]
- Jafari, H.; Hassanpour, M.; Akbari, A.; Rezaie, J.; Gohari, G.; Mahdavinia, G.R.; Jabbari, E. Characterization of pH-sensitive chitosan/hydroxypropyl methylcellulose composite nanoparticles for delivery of melatonin in cancer therapy. Mater. Lett. 2021, 282, 128818. [Google Scholar] [CrossRef]
- Mulcahy, L.A.; Pink, R.C.; Carter, D.R.F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 2014, 3, 24641. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Welsh, J.A.; van der Pol, E.; Bettin, B.A.; Carter, D.R.; Hendrix, A.; Lenassi, M.; Langlois, M.-A.; Llorente, A.; van de Nes, A.S.; Nieuwland, R. Towards defining reference materials for measuring extracellular vesicle refractive index, epitope abundance, size and concentration. J. Extracell. Vesicles 2020, 9, 1816641. [Google Scholar] [CrossRef]
- Rountree, R.B.; Mandl, S.J.; Nachtwey, J.M.; Dalpozzo, K.; Do, L.; Lombardo, J.R.; Schoonmaker, P.L.; Brinkmann, K.; Dirmeier, U.; Laus, R. Exosome Targeting of Tumor Antigens Expressed by Cancer Vaccines Can Improve Antigen Immunogenicity and Therapeutic EfficacyExosome Targeting of Tumor Antigens Improves Efficacy. Cancer Res. 2011, 71, 5235–5244. [Google Scholar] [CrossRef]
- Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011, 29, 341–345. [Google Scholar] [CrossRef] [PubMed]
- Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 2021, 11, 3183. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Dombroski, J.A.; King, M.R. Engineering of exosomes to target cancer metastasis. Cell. Mol. Bioeng. 2020, 13, 1–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gomari, H.; Moghadam, M.F.; Soleimani, M. Targeted cancer therapy using engineered exosome as a natural drug delivery vehicle. OncoTargets Ther. 2018, 11, 5753. [Google Scholar] [CrossRef] [Green Version]
- Rodrigues, P.; Melim, C.; Veiga, F.; Figueiras, A. An Overview of Exosomes in Cancer Therapy: A Small Solution to a Big Problem. Processes 2020, 8, 1561. [Google Scholar] [CrossRef]
- Pascucci, L.; Coccè, V.; Bonomi, A.; Ami, D.; Ceccarelli, P.; Ciusani, E.; Viganò, L.; Locatelli, A.; Sisto, F.; Doglia, S.M. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery. J. Control. Release 2014, 192, 262–270. [Google Scholar] [CrossRef]
- Bonomi, A.; Sordi, V.; Dugnani, E.; Ceserani, V.; Dossena, M.; Coccè, V.; Cavicchini, L.; Ciusani, E.; Bondiolotti, G.; Piovani, G. Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells. Cytotherapy 2015, 17, 1687–1695. [Google Scholar] [CrossRef] [Green Version]
- Toffoli, G.; Hadla, M.; Corona, G.; Caligiuri, I.; Palazzolo, S.; Semeraro, S.; Gamini, A.; Canzonieri, V.; Rizzolio, F. Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. Nanomedicine 2015, 10, 2963–2971. [Google Scholar] [CrossRef]
- Smyth, T.; Kullberg, M.; Malik, N.; Smith-Jones, P.; Graner, M.W.; Anchordoquy, T.J. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release 2015, 199, 145–155. [Google Scholar] [CrossRef] [Green Version]
- Kanchanapally, R.; Deshmukh, S.K.; Chavva, S.R.; Tyagi, N.; Srivastava, S.K.; Patel, G.K.; Singh, A.P.; Singh, S. Drug-loaded exosomal preparations from different cell types exhibit distinctive loading capability, yield, and antitumor efficacies: A comparative analysis. Int. J. Nanomed. 2019, 14, 531. [Google Scholar] [CrossRef]
- Ye, Z.; Zhang, T.; He, W.; Jin, H.; Liu, C.; Yang, Z.; Ren, J. Methotrexate-loaded extracellular vesicles functionalized with therapeutic and targeted peptides for the treatment of glioblastoma multiforme. ACS Appl. Mater. Interfaces 2018, 10, 12341–12350. [Google Scholar] [CrossRef] [PubMed]
- Fukuta, T.; Nishikawa, A.; Kogure, K. Low level electricity increases the secretion of extracellular vesicles from cultured cells. Biochem. Biophys. Rep. 2020, 21, 100713. [Google Scholar] [CrossRef] [PubMed]
- Mendt, M.; Kamerkar, S.; Sugimoto, H.; McAndrews, K.M.; Wu, C.-C.; Gagea, M.; Yang, S.; Blanko, E.V.R.; Peng, Q.; Ma, X. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018, 3, e99263. [Google Scholar] [CrossRef] [PubMed]
- Lin, Y.; Wu, J.; Gu, W.; Huang, Y.; Tong, Z.; Huang, L.; Tan, J. Exosome–liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs. Adv. Sci. 2018, 5, 1700611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Limoni, S.K.; Moghadam, M.F.; Moazzeni, S.M.; Gomari, H.; Salimi, F. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Appl. Biochem. Biotechnol. 2019, 187, 352–364. [Google Scholar] [CrossRef]
- Kamerkar, S.; LeBleu, V.S.; Sugimoto, H.; Yang, S.; 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. [Google Scholar] [CrossRef] [Green Version]
- Haney, M.J.; Klyachko, N.L.; Zhao, Y.; Gupta, R.; Plotnikova, E.G.; He, Z.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A.V. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release 2015, 207, 18–30. [Google Scholar] [CrossRef] [Green Version]
- Lamichhane, T.N.; Jeyaram, A.; Patel, D.B.; Parajuli, B.; Livingston, N.K.; Arumugasaamy, N.; Schardt, J.S.; Jay, S.M. Oncogene knockdown via active loading of small RNAs into extracellular vesicles by sonication. Cell. Mol. Bioeng. 2016, 9, 315–324. [Google Scholar] [CrossRef] [Green Version]
- Sato, Y.T.; Umezaki, K.; Sawada, S.; Mukai, S.-A.; Sasaki, Y.; Harada, N.; Shiku, H.; Akiyoshi, K. Engineering hybrid exosomes by membrane fusion with liposomes. Sci. Rep. 2016, 6, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Goh, W.J.; Lee, C.K.; Zou, S.; Woon, E.C.; Czarny, B.; Pastorin, G. Doxorubicin-loaded cell-derived nanovesicles: An alternative targeted approach for anti-tumor therapy. Int. J. Nanomed. 2017, 12, 2759. [Google Scholar] [CrossRef]
- Fuhrmann, G.; Serio, A.; Mazo, M.; Nair, R.; Stevens, M.M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release 2015, 205, 35–44. [Google Scholar] [CrossRef]
- Wang, Q.; Zhuang, X.; Mu, J.; Deng, Z.-B.; Jiang, H.; Zhang, L.; Xiang, X.; Wang, B.; Yan, J.; Miller, D. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat. Commun. 2013, 4, 1–13. [Google Scholar] [CrossRef] [Green Version]
- Zhang, M.; Xiao, B.; Wang, H.; Han, M.K.; Zhang, Z.; Viennois, E.; Xu, C.; Merlin, D. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Mol. Ther. 2016, 24, 1783–1796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sancho-Albero, M.; del Mar Encabo-Berzosa, M.; Beltran-Visiedo, M.; Fernandez-Messina, L.; Sebastian, V.; Sanchez-Madrid, F.; Arruebo, M.; Santamaria, J.; Martin-Duque, P. Efficient encapsulation of theranostic nanoparticles in cell-derived exosomes: Leveraging the exosomal biogenesis pathway to obtain hollow gold nanoparticle-hybrids. Nanoscale 2019, 11, 18825–18836. [Google Scholar] [CrossRef] [PubMed]
- Podolak, I.; Galanty, A.; Sobolewska, D. Saponins as cytotoxic agents: A review. Phytochem. Rev. 2010, 9, 425–474. [Google Scholar] [CrossRef] [Green Version]
- Yang, T.; Fogarty, B.; LaForge, B.; Aziz, S.; Pham, T.; Lai, L.; Bai, S. Delivery of small interfering RNA to inhibit vascular endothelial growth factor in zebrafish using natural brain endothelia cell-secreted exosome nanovesicles for the treatment of brain cancer. AAPS J. 2017, 19, 475–486. [Google Scholar] [CrossRef]
- Zheng, Z.; Li, Z.; Xu, C.; Guo, B.; Guo, P. Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping. J. Control. Release 2019, 311, 43–49. [Google Scholar] [CrossRef]
- Zhang, D.; Lee, H.; Zhu, Z.; Minhas, J.K.; Jin, Y. Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 2017, 312, L110–L121. [Google Scholar] [CrossRef]
- Munagala, R.; Aqil, F.; Jeyabalan, J.; Gupta, R.C. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016, 371, 48–61. [Google Scholar] [CrossRef] [Green Version]
- Agrawal, A.K.; Aqil, F.; Jeyabalan, J.; Spencer, W.A.; Beck, J.; Gachuki, B.W.; Alhakeem, S.S.; Oben, K.; Munagala, R.; Bondada, S. Milk-derived exosomes for oral delivery of paclitaxel. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 1627–1636. [Google Scholar] [CrossRef]
- Li, Y.; Gao, Y.; Gong, C.; Wang, Z.; Xia, Q.; Gu, F.; Hu, C.; Zhang, L.; Guo, H.; Gao, S. A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal cancer. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 1973–1985. [Google Scholar] [CrossRef] [PubMed]
- Wei, H.; Chen, J.; Wang, S.; Fu, F.; Zhu, X.; Wu, C.; Liu, Z.; Zhong, G.; Lin, J. A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro. Int. J. Nanomed. 2019, 14, 8603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, D.; Zhuang, X.; Xiang, X.; Liu, Y.; Zhang, S.; Liu, C.; 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. [Google Scholar] [CrossRef]
- Gourlay, J.; Morokoff, A.; Luwor, R.; Zhu, H.-J.; Kaye, A.; Stylli, S. The emergent role of exosomes in glioma. J. Clin. Neurosci. 2017, 35, 13–23. [Google Scholar] [CrossRef] [PubMed]
- Ohno, S.-I.; Takanashi, M.; Sudo, K.; Ueda, S.; Ishikawa, A.; Matsuyama, N.; Fujita, K.; Mizutani, T.; Ohgi, T.; Ochiya, T.; et al. Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells. Mol. Ther. 2013, 21, 185–191. [Google Scholar] [CrossRef] [Green Version]
- Kooijmans, S.A.A.; Aleza, C.G.; Roffler, S.R.; van Solinge, W.W.; Vader, P.; Schiffelers, R.M. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. J. Extracell. Vesicles 2016, 5, 31053. [Google Scholar] [CrossRef]
- Smyth, T.; Petrova, K.; Payton, N.M.; Persaud, I.; Redzic, J.S.; Graner, M.W.; Smith-Jones, P.; Anchordoquy, T.J. Surface Functionalization of Exosomes Using Click Chemistry. Bioconjugate Chem. 2014, 25, 1777–1784. [Google Scholar] [CrossRef] [Green Version]
- Zhu, Q.; Ling, X.; Yang, Y.; Zhang, J.; Li, Q.; Niu, X.; Hu, G.; Chen, B.; Li, H.; Wang, Y.; et al. Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy. Adv. Sci. 2019, 6, 1801899. [Google Scholar] [CrossRef]
- Liang, Y.; Xu, X.; Li, X.; Xiong, J.; Li, B.; Duan, L.; Wang, D.; Xia, J. Chondrocyte-targeted microRNA delivery by engineered exosomes toward a cell-free osteoarthritis therapy. ACS Appl. Mater. Interfaces 2020, 12, 36938–36947. [Google Scholar] [CrossRef]
- Yang, J.; Zhang, X.; Chen, X.; Wang, L.; Yang, G. Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol. Ther. Nucleic Acids 2017, 7, 278–287. [Google Scholar] [CrossRef]
- Wang, X.; Chen, Y.; Zhao, Z.; Meng, Q.; Yu, Y.; Sun, J.; Yang, Z.; Chen, Y.; Li, J.; Ma, T. Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction. J. Am. Heart Assoc. 2018, 7, e008737. [Google Scholar] [CrossRef] [Green Version]
- Terasawa, K.; Tomabechi, Y.; Ikeda, M.; Ehara, H.; Kukimoto-Niino, M.; Wakiyama, M.; Podyma-Inoue, K.A.; Rajapakshe, A.R.; Watabe, T.; Shirouzu, M. Lysosome-associated membrane proteins-1 and-2 (LAMP-1 and LAMP-2) assemble via distinct modes. Biochem. Biophys. Res. Commun. 2016, 479, 489–495. [Google Scholar] [CrossRef] [PubMed]
- Bellavia, D.; Raimondo, S.; Calabrese, G.; Forte, S.; Cristaldi, M.; Patinella, A.; Memeo, L.; Manno, M.; Raccosta, S.; Diana, P. Interleukin 3-receptor targeted exosomes inhibit in vitro and in vivo Chronic Myelogenous Leukemia cell growth. Theranostics 2017, 7, 1333. [Google Scholar] [CrossRef] [PubMed]
- Liang, G.; Zhu, Y.; Ali, D.J.; Tian, T.; Xu, H.; Si, K.; Sun, B.; Chen, B.; Xiao, Z. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J. Nanobiotechnology 2020, 18, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Tian, Y.; Li, S.; Song, J.; Ji, T.; Zhu, M.; Anderson, G.J.; Wei, J.; Nie, G. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 2014, 35, 2383–2390. [Google Scholar] [CrossRef]
- Zhou, Y.; Yuan, Y.; Liu, M.; Hu, X.; Quan, Y.; Chen, X. Tumor-specific delivery of KRAS siRNA with iRGD-exosomes efficiently inhibits tumor growth. ExRNA 2019, 1, 1–7. [Google Scholar] [CrossRef] [Green Version]
- Bai, J.; Duan, J.; Liu, R.; Du, Y.; Luo, Q.; Cui, Y.; Su, Z.; Xu, J.; Xie, Y.; Lu, W. Engineered targeting tLyp-1 exosomes as gene therapy vectors for efficient delivery of siRNA into lung cancer cells. Asian J. Pharm. Sci. 2020, 15, 461–471. [Google Scholar] [CrossRef]
- Hung, M.E.; Leonard, J.N. Stabilization of exosome-targeting peptides via engineered glycosylation. J. Biol. Chem. 2015, 290, 8166–8172. [Google Scholar] [CrossRef] [Green Version]
- Ran, N.; Gao, X.; Dong, X.; Li, J.; Lin, C.; Geng, M.; Yin, H. Effects of exosome-mediated delivery of myostatin propeptide on functional recovery of mdx mice. Biomaterials 2020, 236, 119826. [Google Scholar] [CrossRef]
- Liang, G.; Kan, S.; Zhu, Y.; Feng, S.; Feng, W.; Gao, S. Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells. Int. J. Nanomed. 2018, 13, 585. [Google Scholar] [CrossRef]
- Kanuma, T.; Yamamoto, T.; Kobiyama, K.; Moriishi, E.; Masuta, Y.; Kusakabe, T.; Ozasa, K.; Kuroda, E.; Jounai, N.; Ishii, K.J. CD63-mediated antigen delivery into extracellular vesicles via DNA vaccination results in robust CD8+ T cell responses. J. Immunol. 2017, 198, 4707–4715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sung, B.H.; von Lersner, A.; Guerrero, J.; Krystofiak, E.S.; Inman, D.; Pelletier, R.; Zijlstra, A.; Ponik, S.M.; Weaver, A.M. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells. Nat. Commun. 2020, 11, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Cheng, Q.; Shi, X.; Han, M.; Smbatyan, G.; Lenz, H.-J.; Zhang, Y. Reprogramming exosomes as nanoscale controllers of cellular immunity. J. Am. Chem. Soc. 2018, 140, 16413–16417. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, Y.; Nishikawa, M.; Shinotsuka, H.; Matsui, Y.; Ohara, S.; Imai, T.; Takakura, Y. Visualization and in vivo tracking of the exosomes of murine melanoma B16–BL6 cells in mice after intravenous injection. J. Biotechnol. 2013, 165, 77–84. [Google Scholar] [CrossRef]
- Morishita, M.; Takahashi, Y.; Nishikawa, M.; Sano, K.; Kato, K.; Yamashita, T.; Imai, T.; Saji, H.; Takakura, Y. Quantitative analysis of tissue distribution of the B16–BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J. Pharm. Sci. 2015, 104, 705–713. [Google Scholar] [CrossRef]
- Cui, G.-H.; Guo, H.-D.; Li, H.; Zhai, Y.; Gong, Z.-B.; Wu, J.; Liu, J.-S.; Dong, Y.-R.; Hou, S.-X.; Liu, J.-R. RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease. Immun. Ageing 2019, 16, 10. [Google Scholar] [CrossRef] [Green Version]
- Zou, J.; Shi, M.; Liu, X.; Jin, C.; Xing, X.; Qiu, L.; Tan, W. Aptamer-Functionalized Exosomes: Elucidating the Cellular Uptake Mechanism and the Potential for Cancer-Targeted Chemotherapy. Anal. Chem. 2019, 91, 2425–2430. [Google Scholar] [CrossRef]
- Pi, F.; Binzel, D.W.; Lee, T.J.; Li, Z.; Sun, M.; Rychahou, P.; Li, H.; Haque, F.; Wang, S.; Croce, C.M.; et al. Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat. Nanotechnol. 2018, 13, 82–89. [Google Scholar] [CrossRef]
- Cheng, H.; Fan, J.-H.; Zhao, L.-P.; Fan, G.-L.; Zheng, R.-R.; Qiu, X.-Z.; Yu, X.-Y.; Li, S.-Y.; Zhang, X.-Z. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials 2019, 211, 14–24. [Google Scholar] [CrossRef]
- Nakase, I.; Futaki, S. Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Sci. Rep. 2015, 5, 1–13. [Google Scholar] [CrossRef] [Green Version]
- Takayama, Y.; Kusamori, K.; Nishikawa, M. Click chemistry as a tool for cell engineering and drug delivery. Molecules 2019, 24, 172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, M.; Li, J.; Chen, P.R. Transition metal-mediated bioorthogonal protein chemistry in living cells. Chem. Soc. Rev. 2014, 43, 6511–6526. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Zhang, Z. Development and applications of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a bioorthogonal reaction. Molecules 2016, 21, 1393. [Google Scholar] [CrossRef] [PubMed]
- Lee, T.S.; Kim, Y.; Zhang, W.; Song, I.H.; Tung, C.-H. Facile metabolic glycan labeling strategy for exosome tracking. Biochim. Et Biophys. Acta BBA-Gen. Subj. 2018, 1862, 1091–1100. [Google Scholar] [CrossRef] [PubMed]
- 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. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99mTc-HMPAO. Sci. Rep. 2015, 5, 1–10. [Google Scholar] [CrossRef] [Green Version]
- Tian, T.; Zhang, H.-X.; He, C.-P.; Fan, S.; Zhu, Y.-L.; Qi, C.; Huang, N.-P.; Xiao, Z.-D.; Lu, Z.-H.; Tannous, B.A.; et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials 2018, 150, 137–149. [Google Scholar] [CrossRef]
- Jia, G.; Han, Y.; An, Y.; Ding, Y.; He, C.; Wang, X.; Tang, Q. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials 2018, 178, 302–316. [Google Scholar] [CrossRef]
- Koh, E.; Lee, E.J.; Nam, G.-H.; Hong, Y.; Cho, E.; Yang, Y.; Kim, I.-S. Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis. Biomaterials 2017, 121, 121–129. [Google Scholar] [CrossRef]
- Kim, M.S.; Haney, M.J.; Zhao, Y.; Yuan, D.; Deygen, I.; Klyachko, N.L.; Kabanov, A.V.; Batrakova, E.V. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: In vitro and in vivo evaluations. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 195–204. [Google Scholar] [CrossRef]
- Zhou, W.; Zhou, Y.; Chen, X.; Ning, T.; Chen, H.; Guo, Q.; Zhang, Y.; Liu, P.; Zhang, Y.; Li, C.; et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials 2021, 268, 120546. [Google Scholar] [CrossRef]
- Jong, A.Y.; Wu, C.-H.; Li, J.; Sun, J.; Fabbri, M.; Wayne, A.S.; Seeger, R.C. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J. Extracell. Vesicles 2017, 6, 1294368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Watson, D.C.; Bayik, D.; Srivatsan, A.; Bergamaschi, C.; Valentin, A.; Niu, G.; Bear, J.; Monninger, M.; Sun, M.; Morales-Kastresana, A.; et al. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials 2016, 105, 195–205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taylor, D.D.; Shah, S. Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes. Methods 2015, 87, 3–10. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed]
- Hood, J.L.; Scott, M.J.; Wickline, S.A. Maximizing exosome colloidal stability following electroporation. Anal. Biochem. 2014, 448, 41–49. [Google Scholar] [CrossRef] [PubMed]
Active Methods | Examples | Advantages | Limitations | Ref. |
---|---|---|---|---|
physical induction | electroporation | High efficacy and is more efficient than chemical transfection | Depends on cargo types May affect the Zeta potential and colloid stability of exosomes Induce aggregation of siRNAs | [46,47] |
sonication | Compared with co-incubation and electroporation, sonication produces the highest loading efficiency | Damage the EVs structure Must be performed in an ice bath | [48,49] | |
freeze-thaw cycle | Rapid and easy loading | Low loading efficiency, increase the size of EVs, induces aggregation | [50,51] | |
extrusion | Compared with co-incubation, extrusion can produce homogeneous EVs | change the Zeta potential and membrane proteins in EVs | [52,53,54] | |
Chemical induction | ||||
saponins | High loading efficiency | Potential toxicity; cause hemolysis Need extra purification phase | [55,56] | |
liposomes | High loading efficiency, quickly and easily load | Potential toxicity | [57,58] | |
calcium chloride | High loading efficiency simple and stable | Potential toxicity | [59] |
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Akbari, A.; Nazari-Khanamiri, F.; Ahmadi, M.; Shoaran, M.; Rezaie, J. Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization. Pharmaceutics 2023, 15, 66. https://doi.org/10.3390/pharmaceutics15010066
Akbari A, Nazari-Khanamiri F, Ahmadi M, Shoaran M, Rezaie J. Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization. Pharmaceutics. 2023; 15(1):66. https://doi.org/10.3390/pharmaceutics15010066
Chicago/Turabian StyleAkbari, Ali, Fereshteh Nazari-Khanamiri, Mahdi Ahmadi, Maryam Shoaran, and Jafar Rezaie. 2023. "Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization" Pharmaceutics 15, no. 1: 66. https://doi.org/10.3390/pharmaceutics15010066
APA StyleAkbari, A., Nazari-Khanamiri, F., Ahmadi, M., Shoaran, M., & Rezaie, J. (2023). Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization. Pharmaceutics, 15(1), 66. https://doi.org/10.3390/pharmaceutics15010066