Chemically Modified Extracellular Vesicles

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Ahcène Boumendjel	--	2884	2022-04-14 10:17:05	\|
2	format change	Peter Tang	-4 word(s)	2880	2022-04-14 12:30:27	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14030653

Extracellular vesicles (EVs) have been exploited as bio-inspired drug delivery systems (DDS) in the biomedical field. EVs have more advantages than synthetic nanoparticles: they are naturally equipped to cross extra- and intra-cellular barriers. Furthermore, they can deliver functional biomolecules from one cell to another even far away in the body. These advantages, along with obtained promising in vivo results, clearly evidenced the potential of EVs in drug delivery.

extracellular vesicles nanoparticles drug delivery radiolabeling

1. Introduction

Over the decades, minimally invasive synthetic drug delivery systems have been engineered to overcome the limitations of free therapeutics and navigate heterogeneous biological barriers across patient populations and diseases, increasingly needing a personalized clinical intervention for therapeutic efficacy. Synthetic drug delivery systems, as nanoparticles, have also been developed to improve the clearance and distribution profile of a therapeutic intervention that is mainly governed by the vehicle’s character rather than by the drug molecule’s physicochemical properties ^[1]. However, despite the advantages that nanoparticles offer—such as improving stability and solubility of encapsulated cargos, promoting transport across membranes, and prolonging circulation times to increase safety and efficacy for therapeutics delivery ^[2]—their use is still associated with several drawbacks. Notably, a rapid clearance via the reticuloendothelial system ^[3], accumulation in the spleen and liver, and acute hypersensitivity reaction represent the target organ dose ^[4]^[5]. Amongst the continually expanding area of interest in the field of biological or bioinspired drug delivery systems, that of extracellular vesicles (EVs) has been growing expeditiously ^[5]. These heterogeneous populations of naturally occurring nano- to micro-sized membrane vesicles, capable of transporting biomolecules from producer to recipient cells ^[6], have improved the understanding of new forms of cell-cell communication. However, these systems are attractive for turning into commercial products because they have one crucial advantage in common: they come from living cells ^[7]. Most of the current studies employ a few well-characterized cell lines to produce EVs, including microvesicles (MVs), exosomes, or exosome-like vesicles (ELVs) ^[8], and notably stem cells that represent a natural choice because they can be cultured long-term and do not produce an immune response. Recently, a study has reported that specific progenitor cell-derived EVs convey biological cargo promoting angiogenesis and tissue repair and modulating immune functions ^[8]^[9]. This has drawn particular attention towards applying the EVs for therapeutic delivery to overcome synthetic drug delivery systems-associated issues ^[10]. Another intriguing aspect of EVs is their intrinsic stability, circulation, and ability to carry and protect a wide array of nucleic acids into recipient cells, avoiding the mononuclear phagocytic system (MPS) by exhibiting surface protein CD47 ^[11]. It is also significant to highlight that EVs can comprise proteins that bind to and sort their RNA ^[12]. Therefore, EVs represent a promising source for engineering systems to deliver therapeutics under different clinical conditions such as cancer medicine, immunotherapy, and in vivo gene editing. In this regard, genetic modifications of EV-secreting cells have been applied to target restricted cellular receptors. However, this genetic engineering of EV-donor cells appears to be cumbersome and time-consuming. Unfortunately, engineered EV-donor cells are not adequately exposed or adequately stable to act as an efficient drug delivery mechanism that includes multiple steps of cloning, transfection, viral transduction, selection, and large-scale cell culture and EVs purification.

Furthermore, although it can enable stable conjugation of EVs with targeting moieties, genetic manipulation poses a high risk of horizontal gene transfer because the process may incorporate high-copy plasmids or transgenes that are eventually transferred to target cells. Even though different approaches requiring genetic modification of EV-secreting cells have been applied to overcome these complications, they still suffer from the same limitations described above for EV-donor cells. Therefore, a series of alternative methods addressing the modification of EVs after secretion without manipulating the EV-producing cells are still needed to avoid genetic manipulation. In this regard, recent studies have provided evidence that click chemistry can be efficiently used to modify EV-producing cells ^[13] or purified EVs ^[14] to generate “tailored” vesicles.

2. Chemical Modification for In Vivo Tracking Extracellular Vesicles

Several limitations for in vivo tracking of EVs, such as poor penetration depth and spatial resolution, make it unsuitable for their complete clinical translation. Nuclear medicine imaging could be a good option for tracking EVs and evaluating their biodistribution. This method provides three-dimensional images using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). Furthermore, nuclear imaging combined with anatomical imaging, such as computed tomography (CT) or MRI, represents a good option for providing better tracking of the localization of the EVs. This approach provides excellent sensitivity and more straightforward quantification, making their clinical applications feasible. However, it is equally important to stress that one significant restriction of this nuclear imaging technology is the possibility of altering EVs proprieties by the transduction procedure. EV subpopulations, such as exosomes and microvesicles, have physiological properties suitable for radio imaging. Indeed, the primordial role of EVs is in long-distance cell–cell communication because the secreted EVs can enter circulation and pass through additional biological barriers, making them suitable for real-time monitoring in their native environments ^[9]^[10]. An efficient strategy for EVs conjugation with a radionuclide could provide an enhanced understanding of EVs’ functions in the physiology and pathophysiology of many diseases. Likewise, the characterization of their pharmacokinetics and biological behavior could be constructive for fostering improved diagnoses and treatment of many pathologies. Because nuclear imaging modalities can also provide information about the therapeutic dose of EVs and their potential side effects ^[15], definite chemical modifications are needed within the EVs research field to overcome the radiolabeling-associated drawbacks and enhance their use for in vivo tracking.

3. Chemical Modifications on Extracellular Vesicle-Mediated Delivery Cargo

EVs have emerged as a powerful tool for drug delivery, including their intrinsic homing ability, biocompatibility, cell-specific targeting, non-immunogenicity, broad distribution in biological fluids, and easy penetration across physiological barriers ^[6]^[7]. However, one of the significant limitations of EV-based drug delivery has been the lack of efficient isolation methods. In particular, conventional EV isolation techniques have limited yields, low purity, and inadequate batch-to-batch consistency. Therefore, chemical modifications have been developed to exploit EV drug delivery potential, introduce and stabilize the cargo of exogenous origin into EVs, and maximize their efficacy of targeting and delivery.

3.1. Covalent Binding Approach

Click chemistry can also improve the intracellular delivery of therapeutic EV cargo. Click chemistry is used to alter the character of EVs surface. Smyth et al. tested whether the linkage of azide-fluor 545 on the surface of an EV would change its function ^[14]. For such purpose, first, exosomes derived from 4T1 breast cancer cells were functionalized with a terminal alkyl group. Then, the amine group present on the 4T1 derived EVs’ surface was cross-linked with the carboxyl group of a 4-pentynoic acid using carbodiimide activation ^[14]. This enabled the conjugation of the 4T1-derived EVs with azide-fluor 545 thanks to click chemistry. It was reported that the chemical modification impaired no modification of the natural functions of the EV, and as expected, the copper catalyst was potentially cytotoxic ^[10].

Nonetheless, click chemistry tends to be time-consuming and requires reaction conditions that are difficult to master ^[16]^[17]^[18]. Those limitations motivated investigators to conjugate an aptamer on the surface of EVs using covalent binding with another method than click chemistry. This method was applied in improving the delivery of the anticancer drug paclitaxel to target cancer cells ^[17]. This innovative method covalently modifies the surface of a dendritic cell-derived EVs loading paclitaxel (PTX). The surface modification showed a 6-fold and 3-fold treatment efficacy in vitro and in vivo, respectively, compared with unmodified PTX-loaded EVs. Moreover, the added cholesterol could also confer the EVs better rigidity and stability by enhancing the hydrophobic–hydrophobic interactions in lipid bilayers ^[19]. Finally, it was claimed that a significant amount of EVs could be prepared in approximately one hour. All these advantages favor the clinical translation of this method in the future.

Similarly, it was suggested to study a permanent covalent bond between peptides or specific nanobodies and EVs’ surfaces. Thanks to a simple enzymatic method on EVs targeting several cancer cells, this bond was possible. EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody improved their accumulation in EGFR+ cancer cells. This occurs in vitro as well as in vivo ^[20]. Interestingly, this enzymatic method using protein ligases is also efficient on EVs with peptides and nanobodies targeting other receptors. This method is not specific to a defined type of receptor. It could be worthwhile to know whether this method could apply with a more prominent protein of interest. Moreover, the modified EVs could also efficiently deliver paclitaxel or RNA to cancer cells (Table 1).

Table 1. Summary of the studies dealing with chemical modifications of extracellular vesicle-mediated delivery cargo using covalent binding approaches.

Source of Exosomes	Purpose	Method	Results	References
4T1 breast cancer-derived exosomes	See whether the linkage of azide-fluor 545 on the surface of an EV would change its function	4T1 EXOs were functionalized with a terminal alkyl group after click chemistry	No modification of the natural functions of the EV was impaired by being chemically modified	^[14]
Dendritic cell-derived EVs	Improving the delivery of paclitaxel to target cancer cells	Conjugation of an aptamer on the surface of EVs using covalent binding	The surface modification showed a 6-fold and 3-fold treatment efficacy in vitro and in vivo	^[17]
Human red blood cells (RBCs) as a source of EVs	Study of a permanent covalent bond between peptides or specific nanobodies and EVs’ surfaces	Simple enzymatic method on EVs targeting several cancer cells	Epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody improved their accumulation in EGFR+ cancer cells	^[20]

Hence, it can be concluded that the modeling of covalent bonds on EVs could allow their use not only in preclinical stages but potentially in humans.

3.2. Non-Covalent Binding

Two main non-covalent binding methods were reported. The first one consisted of the bond between EVs and surface peptides thanks to electrostatic interaction. An alternative approach was proposed to influence the delivery of exosomes with magnetic strength. Hence, Nakase and Futaki explored a simple technique for enhancing exosomes’ cellular uptake and cytosolic release ^[21]. They combined a pH-sensitive fusogenic GALA peptide with a commercially available cationic lipid: lipofectamine (LTX). The electrostatic interaction occurred between the positively charged LTX and the negatively charged surface membrane of a CD63-green fluorescent protein (GFP)-tagged exosome. To study the cellular uptake, HeLa and CHO-K1 cells were treated with the GFP-GALA-Exos with and without the addition of lipofectamine. It was found that 4% of LTX increased the cellular uptake of GFP-GALA-Exos 15-fold by HeLa cells and 175-fold by CHO-K1 cells. Unfortunately, a higher LTX concentration could induce cytotoxicity.

Thus, an alternative was studied to check whether a lower dose of added LTX could always increase the cellular uptake, and indeed it did. The addition of 2.0% LTX increased the cellular uptake by six-fold. This encouraging result led to encapsulating dextran in GFP-GALA-LTX-Exos, and the result was an increase in cellular absorption and drug release ^[21]. Tamura and colleagues worked on EVs whose surface was modified with cationized pullulan (commonly named pull+) ^[22]. Pullulan can target hepatocyte asialoglycoprotein (ASGPR) receptors ^[23], and this property will help exosomes conjugated with cationized pullulan reach injured liver sites. The +pull-Exos were easily internalized in HepG2 cells, reflecting an excellent cellular uptake. After systemic administration in mice with concanavalin A-induced liver injuries, +pull-Exos were distributed readily in the liver.

The necrotic areas were at their lowest in these same regions, which shows an enhanced anti-inflammatory effect of +pull-Exos ^[22]—adding cationic agents positively impacted drug delivery. It would still be necessary to monitor the concentration of these cationic agents to avoid and prevent cytotoxicity.

Concerning the magnetic method, Maguire et al. managed a study on using streptavidin-conjugated magnetic beads to influence the targeting of a new kind of microvesicles ^[24]. During the production of adeno-associated viruses (AAV), it seems that they are naturally associated with nearby exosomes and form so-called vexosomes ^[24]^[25]. These new nanoscale vehicles are less immunogenetic and more biocompatible than normal AAVs. Those mRNAs containing vexosomes were bound to magnetic beads to see whether they could react to the attraction of a magnetic field. Hence, small magnets adhered to one region of the numerous well plates that were used. The strategy was applied to biotin acceptor peptide transmembrane domain (BAP-TM) receptors to be incorporated by the vexosomes to allow their specific cell targeting and eventual binding to biotinylated ligands via a streptavidin bridge. This streptavidin bridge then reacted with the streptavidin-conjugated magnetic beads. It was found that after activation of the magnetic field, two times more vexosomes joined the magnetic region, suggesting a more specific targeting by the streptavidin-conjugated magnetic exosome when biotinylated ligand was expressed on the microvesicles surface ^[24]. With the encouraging in vitro results, this promising method needs to be confirmed in vivo. In this context, Qi et al. carried out an in vivo study of blood-derived exosomes endowed with magnetic properties as a new targeted drug delivery system in cancer therapy ^[26]. Hence, they developed a dual-functional reticulocyte-derived exosome-based superparamagnetic nanoparticle cluster (SMCNC-Exo) through transferrin conjugated SMCNCs bound to the transferrin of reticulocyte-derived exosomes. The SMCNC-Exo was loaded with doxorubicin via hydrophobic effects. This drug-loaded SMCNC-Exo (D-SMCNC-Exo) was described as biocompatible for drug delivery.

Regarding in vitro drug release, at pH 7.4, approximatively 80% of doxorubicin was released after 8 h. Concerning the in vivo biodistribution in hepatoma 22 subcutaneous cancer-bearing mice, after applying a magnetic field (MF), D-SMCNC-Exos were 1.7-fold more at the cancer site than without the MF. Doxorubicin-SMCNC-Exo succeeded in slightly inhibiting the growth factor without the help of a magnetic field. Still, the entire suppression of the tumor growth factor was possible only under MF ^[26] (Table 2).

Table 2. Summary of the studies dealing with chemical modifications on extracellular vesicle-mediated delivery cargo using non-covalent binding approaches.

Source of Exosomes	Purpose	Method	Results	References
CD63-GFP-containing exosomes derived from HeLa cells and Chines Hamster Ovary (CHO)-K1 cells	A simple technique for enhancing exosomes cellular uptake and cytosolic release	Electrostatic interaction between a positively charged lipofectamine and the negatively charged surface membrane of an EV	LTX increased the cellular uptake of GFP-GALA-Exos 15-fold by HeLa cells and 175-fold by CHO-K1 cells	^[21]
Mesenchymal stem cells (MSC)-derived exosomes	Reach injured liver sites	EVs surface modified with cationized pullulan	Excellent cellular uptake in HepG2 cells and good distribution in the liver Enhanced anti-inflammatory effect of +pull-MSC Exos	^[22]
Vexosomes are formed by the natural association between adeno-associated viruses and exosomes	Influence of magnetic beads on the targeting of vexosomes	Vexosomes were bound to streptavidin-conjugated magnetic beads	After activation of the magnetic field, two times more vexosomes joined the magnetic region	^[24]
Reticulocyte-derived exosomes (REXOs)	Study of a new targeted drug delivery system	Transferrin conjugated superparamagnetic nanoparticle cluster bound to the transferrin of REXOs loaded with doxorubicin via hydrophobic effects	The entire suppression of the tumor growth factor was possible only under MF	^[26]

3.3. Hydrophobic Insertion

EVs’ last chemical modification method concerns the insertion of hydrophobic molecules on the membrane of exosomes or exosome-like vehicles. As the membrane of EVs is made of a phospholipid bilayer, it is possible to modulate this property to improve the use of EVs as drug delivery vehicles. In this context, Kim et al. developed an in vivo study of the engineering of macrophage (stemming from the primary bone marrow)-derived exosomes for targeted paclitaxel delivery to pulmonary metastases ^[27]. Paclitaxel-loaded macrophage-derived exosomes with incorporated aminoethylanisamide-PEG (AA-PEG) could bind specifically to the sigma receptors overexpressed in lung cancer cells; aminoethylanisamide is a ligand of sigma receptors. It seems that after the injection in mice with pulmonary metastases, AA-PEG-PTX-Exos showed greater antineoplastic efficacy than Taxol or PTX-Exos. Furthermore, the modulated exosome provides the eradication of pulmonary metastasis because of the high inhibition of tumor growth of AA-PEG-PTX-Exos. This innovative method based on aminoethylanisamide-PEG hydrophobic insertion improved the loading capacity of paclitaxel and its accumulation in cancer cells upon systemic administration, and it is a more excellent therapeutic outcome ^[27].

The second study concerns the hydrophobic insertion of cholesterol to improve exosome-based cancer therapy’s therapeutic effects ^[28]. Their key feature of the method relies on an RNA aptamer–protein interaction after the loading of anticancer molecules by a reversible light-inducible protein-protein interaction and the remodeling of the exosome’s producer cells (Table 3). Thus, AS1411 aptamer modified the surface of exosomes because of its hydrophobic membrane, which can interact with cholesterol. This hydrophobic insertion induced a good internalization of the exosomes in K562 leukemia cells. In addition, the AS1411-Exos contained microRNA-21 sponges, which are inhibitors of miR21 in K562 cells, contributing to cancer initiation, progression, and metastasis ^[28]^[29]. In the latter study’s frame, the successful delivery of AS1411-miRNA21-Exos was translated by significant inductions of cellular apoptosis ^[28].

Table 3. Description of the studies dealing with chemical modifications on extracellular vesicle-mediated delivery cargo using hydrophobic insertion approaches.

Source of Exosomes	Purpose	Method	Results	References
Primary bone marrow stemmed macrophage-derived exosomes	Targeting of paclitaxel delivery to pulmonary metastases for systemic administration	Incorporation of amino-ethylanisamide-PEG on the surface of EXOs allows the bond of the sigma receptors to lung cancer cells	Greater antineoplastic efficacy, high inhibition of tumor growth, and better survival time after systemic administration	^[27]
Plasma-derived exosomes containing miRNA21	Hydrophobic insertion of cholesterol to improve the therapeutic effects of exosome-based cancer therapy	Modification of loaded exosomes with the hydrophobic insertion of AS1411 aptamer interacting with proteins after a reversible light-inducible protein-protein interaction	Good internalization of the exosomes in leukemia cells and successful delivery of the miRNA21 loaded AS1411-Exos with significant induction of cellular apoptosis	^[28]

References

Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; del Pilar Rodriguez-Torres, M.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71.
Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 2020, 20, 101–124.
Tyagi, A.; Sharma, P.K.; Malviya, R. Role of blood retinal barrier in drug absorption. Pharm. Anal. Acta 2018, 9, 5.
Anselmo, A.; Gupta, V.; Zern, B.J.; Pan, D.; Zakrewsky, M.; Muzykantov, V.; Mitragotri, S. Delivering Nanoparticles to Lungs while Avoiding Liver and Spleen through Adsorption on Red Blood Cells. ACS Nano 2013, 7, 11129–11137.
De Jong, W.H.; Borm, P.J. Drug delivery and nanoparticles: Applications and hazards. Int. J. Nanomed. 2008, 3, 133–149.
Luo, R.; Liu, M.; Tan, T.; Yang, Q.; Wang, Y.; Men, L.; Zhao, L.; Zhang, H.; Wang, S.; Xie, T.; et al. Emerging Significance and Therapeutic Potential of Extracellular vesicles. Int. J. Biol. Sci. 2021, 17, 2476–2486.
Orefice, N. Development of New Strategies Using Extracellular Vesicles Loaded with Exogenous Nucleic Acid. Pharmaceutics 2020, 12, 705.
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.
Jansen, F.; Li, Q.; Pfeifer, A.; Werner, N. Endothelial- and Immune Cell-Derived Extracellular Vesicles in the Regulation of Cardiovascular Health and Disease. JACC Basic Transl. Sci. 2017, 2, 790–807.
Man, K.; Brunet, M.Y.; Jones, M.-C.; Cox, S.C. Engineered Extracellular Vesicles: Tailored-Made Nanomaterials for Medical Applications. Nanomaterials 2020, 10, 1838.
Dang, X.T.T.; Kavishka, J.M.; Zhang, D.X.; Pirisinu, M.; Le, M.T.N. Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery. Cells 2020, 9, 2191.
Sork, H.; Corso, G.; Krjutskov, K.; Johansson, H.J.; Nordin, J.; Wiklander, O.P.B.; Lee, Y.X.F.; Westholm, J.O.; Lehtiö, J.; Wood, M.J.A.; et al. Heterogeneity and interplay of the extracellular vesicle small RNA transcriptome and proteome. Sci. Rep. 2018, 8, 10813.
Wang, M.; Altinoglu, S.; Takeda, Y.S.; Xu, Q. Integrating Protein Engineering and Bioorthogonal Click Conjugation for Extracellular Vesicle Modulation and Intracellular Delivery. PLoS ONE 2015, 10, e0141860.
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.
György, B.; Hung, M.E.; Breakefield, X.O.; Leonard, J.N. Therapeutic Applications of Extracellular Vesicles: Clinical Promise and Open Questions. Annu. Rev. Pharmacol. Toxicol. 2015, 55, 439–464.
Wang, C.-F.; Mäkilä, E.; Kaasalainen, M.H.; Liu, D.; Sarparanta, M.; Airaksinen, A.J.; Salonen, J.J.; Hirvonen, J.T.; Santos, H.A. Copper-free azide–alkyne cycloaddition of targeting peptides to porous silicon nanoparticles for intracellular drug uptake. Biomaterials 2013, 35, 1257–1266.
Wan, Y.; Wang, L.; Zhu, C.; Zheng, Q.; Wang, G.; Tong, J.; Fang, Y.; Xia, Y.; Cheng, G.; He, X.; et al. Aptamer-Conjugated Extracellular Nanovesicles for Targeted Drug Delivery. Cancer Res. 2018, 78, 798–808.
Brennan, J.L.; Hatzakis, N.; Tshikhudo, T.R.; Dirvianskyte, N.; Razumas, V.; Patkar, S.; Vind, J.; Svendsen, A.; Nolte, R.; Rowan, A.; et al. Bionanoconjugation via Click Chemistry: The Creation of Functional Hybrids of Lipases and Gold Nanoparticles. Bioconjugate Chem. 2006, 17, 1373–1375.
Moghimi, S.M.; Patel, H.M. Tissue specific opsonins for phagocytic cells and their different affinity for cholesterol-rich liposomes. FEBS Lett. 1988, 233, 143–147.
Pham, T.C.; Jayasinghe, M.K.; Pham, T.T.; Yang, Y.; Wei, L.; Usman, W.M.; Chen, H.; Pirisinu, M.; Gong, J.; Kim, S.; et al. Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery. J. Extracell. Vesicles 2021, 10, e12057.
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, 10112.
Tamura, R.; Uemoto, S.; Tabata, Y. Augmented liver targeting of exosomes by surface modification with cationized pullulan. Acta Biomater. 2017, 57, 274–284.
Kanatani, I.; Ikai, T.; Okazaki, A.; Jo, J.-I.; Yamamoto, M.; Imamura, M.; Kanematsu, A.; Yamamoto, S.; Ito, N.; Ogawa, O.; et al. Efficient gene transfer by pullulan–spermine occurs through both clathrin- and raft/caveolae-dependent mechanisms. J. Control. Release 2006, 116, 75–82.
Maguire, C.A.; Balaj, L.; Sivaraman, S.; Crommentuijn, M.H.; Ericsson, M.; Mincheva-Nilsson, L.; Baranov, V.; Gianni, D.; Tannous, B.A.; Sena-Esteves, M.; et al. Microvesicle-associated AAV Vector as a Novel Gene Delivery System. Mol. Ther. 2012, 20, 960–971.
Khan, N.; Maurya, S.; Bammidi, S.; Jayandharan, G.R. AAV6 Vexosomes Mediate Robust Suicide Gene Delivery in a Murine Model of Hepatocellular Carcinoma. Mol. Ther. Methods Clin. Dev. 2020, 17, 497–504.
Qi, H.; Liu, C.; Long, L.; Ren, Y.; Zhang, S.; Chang, X.; Qian, X.; Jia, H.; Zhao, J.; Sun, J.; et al. Blood Exosomes Endowed with Magnetic and Targeting Properties for Cancer Therapy. ACS Nano 2016, 10, 3323–3333.
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. Nanomedicine 2018, 14, 195–204.
Huang, L.; Gu, N.; Zhang, X.-E.; Wang, D.-B. Light-Inducible Exosome-Based Vehicle for Endogenous RNA Loading and Delivery to Leukemia Cells. Adv. Funct. Mater. 2019, 29, 1807189.
Kumarswamy, R.; Volkmann, I.; Thum, T. Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011, 8, 706–713.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Nanoscience & Nanotechnology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Ahcène Boumendjel

View Times: 387

Update Date: 14 Apr 2022

Table of Contents

Video Upload Options

Confirm