. 2021 Nov 24;7(2):e10269. doi: 10.1002/btm2.10269

Tango of dual nanoparticles: Interplays between exosomes and nanomedicine

Yabin Wang ^1,², Wenzhen Wang ³, Fangong Kong ¹, Qiu Zhang ⁴, Jiaqi Xiao ², Yi Zhang ^5,^✉, Bing Yan ^6,^✉

PMCID: PMC9115704 PMID: 35600647

Abstract

Exosomes are lipid bilayer vesicles released from cells as a mechanism of intracellular communication. Containing information molecules of their parental cells and inclining to fuse with targeted cells, exosomes are valuable in disease diagnosis and drug delivery. The realization of their clinic applications still faces difficulties, such as lacking technologies for fast purification and functional reading. The advancement of nanotechnology in recent decades makes it promising to overcome these difficulties. In this article, we summarized recent progress in utilizing the physiochemical properties of nanoparticles (NPs) to enhance exosome purification and detection sensitivity or to derive novel technologies. We also discussed the valuable applications of exosomes in NPs‐based drug delivery. Till now most studies in these fields are still at the laboratory research stage. Translation of these bench works into clinic applications still has a long way to go.

Keywords: exosome, nanomedicine, nanoparticle, targeted drug delivery

Most eukaryotic cells secrete bilayer lipid vesicles named exosomes to maintain intracellular material hemostasis and intercellular communication. Exosomes originate from the endosomal compartments and are released from cells when fused with plasma membrane. Typically having a diameter of ~40–160 nm, exosomes are heterozygous in size and composition. The components, including information molecules such as DNAs, mRNAs, miRNAs, proteins, and lipids, are restrained inside or on the surface depending on their origin. Recent studies have shown that these information molecules retain the physiological status and functions of their parental cells. ¹ , ² Exosomes are ubiquitously found in almost all body fluids, such as blood, urine, saliva, breast milk, and cerebrospinal fluid, therefore they are valuable liquid biopsy biomarkers that are easily accessible for early disease diagnosis and prognosis. ³ , ⁴ Because of these reasons, exosomes are extensively studied in recent years for potential clinical applications.

As an important mechanism of intercellular communication, exosomes mediate material exchange among cells by fusing with recipient cells and transmit their cargos into them, a process leading to disease advancing or restraining. ⁵ , ⁶ Because of the homology, exosomes fuse with target cells in a high efficiency without causing undesirable side effects. Moreover, since they are highly biocompatible, there is little concern about the consequence of their ADME (absorption, distribution, metabolism, and excretion), ⁷ which is usually an important safety issue when artificial nanoparticles (NPs) like polymers are used for the same aim. ⁸ Therefore, exosomes are also regarded as intriguing natural drug delivery carriers. ⁹ , ¹⁰ , ¹¹ , ¹²

The studies of exosomes confront technique difficulties. Analysis techniques with high sensitivity and specificity are currently lacking, thus in order to achieve quantitative analysis for clinic applications, a large pool of purified exosomes is usually required. However, the exosome purification technologies available now are far from satisfactory. Some studies showed that the methods used for exosome purification affect their heterogeneity, raising the concern about the fidelity of the purified exosomes to reflect the in vivo natural status. ¹³ , ¹⁴ , ¹⁵ Moreover, some widely used methodologies based on the recognition of surface markers are recently found to as well enrich other multiple vesicle bodies like ectosomes. ¹⁶ Therefore, more efficient and exosome‐specific purification and highly sensitive detection methods are eagerly required. An intriguing clinical application of exosomes is for drug delivery. ¹⁷ For this aim, adequate exosomes must be produced from source cells and appropriate surface modifications are usually desired. ¹⁸ Till today, approaches used for realizing these aims are unmature and have much room for improvement.

Nanotechnology has been widely explored in different fields of biomedicine in recent decades. ¹⁹ , ²⁰ Properties of varieties of NPs, like high specific surface area, ²¹ unique optical effects, ²² and superparamagnetism, ²³ make them highly promising to revolutionize exosome studies. On one hand, nanotechnology provides novel strategies for exosome biogenesis regulation, purification, and analysis, making more sensitive and accurate functional readings possible. ²⁴ On the other hand, it helps to broaden the scope of exosome applications in biomedicine, which is impractical by traditional technologies. ²⁵ , ²⁶ Some significant progresses have been made in these fields in recent years. In this article, we will summarize the recent progress in NPs' applications for exosome biogenesis control, purification, quantitative detection, and manipulation for medical aims.

1. NPS FOR EXOSOME BIOGENESIS REGULATION

Recent studies indicated that exosomes play critical roles in regulation of normal physiological processes like pregnancy, ²⁷ , ²⁸ development and immune response, ²⁹ as well as in pathogenesis ³⁰ and disease progression. ³¹ , ³² Exosomes are also found to be associated with diseases like neurodegenerative and cardiovascular diseases and tumors. ⁵ Because of this, modification of exosome biogenesis appears as a way of maintaining healthy physiology and preventing disease progression. The accumulated knowledge about the exosome biogenesis opens novel ways to manipulate major steps and factors in this process. ¹ , ³³ , ³⁴ , ³⁵

NPs have been reported to modulate exosome attributes. In one study, gold NPs (AuNPs) of 5 nm stimulated mouse embryonic stem cells to secrete exosomes which are distinct from the natural ones since they have higher rigidity and different protein expression profile. ³⁶ Moreover, unlike those produced in nontreated cells, these exosomes did not promote tumor cell migration in breast tumor cell model 4 T1, probably because they did not stimulate the expression or phosphorylation of metastasis‐promoting proteins like cofilin and extracellular regulated protein kinases (ERKs). ³⁶ This study suggests the possibility of employing NPs to host cells to produce safer exosomes as drug delivery carriers.

One widely used approach for exosome biogenesis regulation is to manipulate protein expression of important regulator genes involved in the process of exosome generation and conveyance. ³⁷ To do this, silencing molecules like siRNAs or antisense oligonucleotides or exogenous DNAs are usually applied. ³⁸ However, delivery of these molecules confronted low efficiency due to the lack of appropriate carriers. NPs have a high drug loading capability and are promising to break this limit. GTPase family proteins play important roles in multiple steps of vesicle trafficking including budding, docking, and fusion, thus are important regulators of exosome secretion. ³⁹ By carrying antisense oligonucleotides targeting a GTPase family member RAB27A, AuNPs significantly lessened exosome release from MCF‐7 and MDA‐MB‐453 cells. ⁴⁰ And the functionalized AuNPs can be carried over to the recipient cells by the secreted exosomes and continue to execute gene silencing. These pilot studies highlight the possibility of using NPs to regulate exosome biogenesis aiming to limit tumor metastasis.

Naturally, cells produce a small number of exosomes, which forms the major limitation of their therapeutic applications. In order to enhance the production, some mechanical methods, like iterative physical extrusion or freeze/thaw cycle have been reported. ⁴¹ , ⁴² A disadvantage of these methods is that the integrity of exosome membrane may be damaged. NPs have been enforced to stimulate higher exosome yield in cells. In one study, platinum NPs treatment induced six folds higher exosome production in cancer cells via an oxidative stress‐mediated mechanism. ⁴³ In another study, porous silicon NPs promoted autophagosome formation in human hepatocarcinoma cell line when used as a drug delivery carrier and stimulated 34 times more exosomes release. ⁴⁴ Positively charged iron oxide NPs entered mesenchymal stem cells via a dynamin‐dependent endocytosis mechanism, and in cells, they enhanced exosome secretion by stimulating the expression of factors involved in autophagosome and autolysosome formation including Beclin‐1 and Rab7. ⁴⁵ These studies showed that application of NPs is an easy and highly efficient way to improve exosome production.

Although the above success, when NPs were applied to cells, the increased exosome yield is often accompanied by cellular toxicity mediated by induction of oxidative stress and autophagy. ⁴³ , ⁴⁴ This cellular toxicity consequently decreased source cell viability and the alteration of exosome attributes, as well as leave stress markers in exosome cargos which may affect recipient cell physiology when exosomes are used as theragnostic delivery carriers. ⁴⁵ So in future, one of the study aims is to develop efficient NPs to stimulate exosome release but with minimal side effects to exosome‐derived cells.

2. NPS FOR EXOSOME PURIFICATION

Based on the difference in physiochemical and biological properties between exosomes and other components in the biological fluids, exosomes are traditionally purified by approaches including ultracentrifugation, ultrafiltration, precipitation, size‐exclusion chromatography, or immunoaffinity capture. These approaches have their own advantages and disadvantages (Table 1 ). The applications of NPs for exosome purification are mostly used in immunoaffinity capture. In this use, antibodies or aptamers targeting exosome surface molecules (mainly proteins or lipids) are conjugated to NPs. There are two attractive advantages when NPs are used for this purpose. First, because of the high specific surface area, a large amount of targeting molecules can be conjugated, thus enhance the binding affinity with exosomes. Second, varieties of NPs with different functions can be combined to form a multiply functionalized nano‐platform for realization of simultaneous isolation and quantification. Because of these advantages, exosomes can be purified under a mild condition in a more efficient manner. For example, by applying magnetic NPs, folate functionalized exosomes can be isolated with a high specificity in less than 2 h, compared to at least 4 h by applying ultracentrifugation. ⁵² Another example is that Fe₃O₄@TiO₂ NPs were used for exosome purification taking advantage of the binding between phospholipids of exosomes and TiO₂ shell. By applying an exogenous magnetic field, 96.5% of exosomes can be purified within 5 min, an efficiency higher than any reported traditional approaches. And after simple wash step, the high enriched exosomes can be used for the following‐up quantification step. ⁵³ By using antibody‐conjugated magnetic nanowires, exosomes were isolated in less than 1 h and the purification yield reached more than 10 times than that obtained by ultracentrifugation (~150 × 10⁸ vs. ~10 × 10⁸ exosomes/ml). ⁵⁴

TABLE 1.

The advantages and disadvantages of protocols for exosome purification

Separation method	Principle	Advantages	Disadvantages	Reported yield	References
Ultracentrifugation	Speed related to the particle size/density	High purity, large volumes	Special equipment required; tedious process， time‐consuming (3–18 h)	275 μg/mg	[46, 47]
Immunoaffinity Capture	Specific binding between immobilized antibody and antigens on exosomes	High specificity/ purity and sensitivity; fast (1.5 h)	High cost; small volume (0.5 ml)	117 μg/mg	[47]
Size‐exclusion chromatography	Exosome size determines retention time	Simple operation; high purity; retention of biological activity; fast (0.5 h)	Dilution of sample required	1.0 × 10¹²/ml	[48]
Ultrafiltration	Membrane intercept	Simple operation; large volume; fast (0.5 h)	Low purity, membrane damage	2 × 10¹⁰ /10⁶ cells	[49]
Polymer‐based Precipitation	Exosome solubility/dispersion changed by polymers	Simple operation; large sample volume, 0.5 –12 h	Lower activity of exosome, low purify	4.5 × 10¹⁰/ml	[50]
Microfluid‐based techniques	Fluid channels are designed according to the characteristics of exosomes	High sensitivity and low cost, high purify; fast (0.5 h)	Difficultly in handling large sample	NA	[51]

Open in a new tab

The most widely used property of NPs is their superparamagnetism produced by magnetic NPs (Figure 1a). ⁵² The targeting moieties can be any molecules natural to cells, like transferrin receptors from blood cells, ⁵⁵ or those designed to be carried by exosomes by a donor cell‐assisted membrane modification strategy, ⁵² such as biotin (streptavidin as ligand) or folic acid (folic acid receptor as ligand).

Mechanism of magnetic or TiO₂‐based exosome isolation. (a) Schematic illustration of the isolation of streptavidin‐modified iron oxide nanoparticles (SA‐IONPs)/exosomes. By conjugation with SA‐IONPs, cell‐derived exosomes can be efficiently isolated from the supernatant using magnetic activated sorting (Image reprinted with permission from Reference [52]. (b) Mechanism of exosomes captured by Fe₃O₄@TiO₂. Enrichment of exosomes is achieved via the bidentate binding between the phosphate groups on the surface of exosome and TiO₂ (Image reprinted with permission from Reference [53]. (c) An illustration showing the antibody cocktail‐conjugated magnetic nanowires used for the isolation of circulating exosomes (image reprinted with permission from Reference [54])

When used for exosome purification, magnetic NPs can be directly modified on their surface by targeting molecules. For example, transferrin molecules were covalently conjugated to Fe₃O₄ NPs surface and used to isolate transferrin receptor positive exosomes in a magnetic field. ⁵⁵ Magnetic NPs can also be further modified using different types of NPs to form a multiply functionalized platform. For example, Fe₃O₄ NPs can be coated by TiO₂ NPs to form a composite with core‐shell structures, taking advantage of strong binding affinity between TiO₂ with hydrophilic phosphoric acid of exosomes. This composite can be used to realize aptamer‐free exosome isolation (Figure 1b). ⁵³ Fe₃O₄@Gold core‐shell NPs were also developed. In this composite, gold shell surface was conjugated with aptamers to specifically recognize exosome surface markers, and also serves as a SERS test tag. ⁵⁶ Moreover, detection tags, like AuNPs for surface‐enhanced Raman scattering (SERS) immunoassay, can be added to NPs surface for in situ quantification without the requirement of elution, a critical step to lose the isolated samples. Magnetic nanowires doped inside with magnetic nanospheres were used to efficiently catch circulating exosomes (Figure 1c). ⁵⁴ The thermal responsibility of magnetic NPs was also used for exosome purification. ⁵⁷

NPs may also aid exosome purification by other mechanisms. Recent studies find that nanometer scale topography can be used for tumor cells or cell−/sub‐cell size organisms (like bacteria) capture based on cell‐nanostructure interaction. ⁵⁸ This emerges as an important mechanism underlying microfluidic chip technology. ⁵⁹ , ⁶⁰ , ⁶¹ By using manufacturable silicon processes, an array with uniform nanoscale gap sizes can be produced, which has been reported to efficiently separate exosomes. ⁶² NPs like graphene oxide are good candidates to be used as coating materials to make nano‐interfaces with enhanced capture area while suppressing nonspecific adsorption. ⁶³ , ⁶⁴

3. NPS FOR QUANTITATIVE EXOSOMES DETECTION

Exosomes are valuable liquid biopsy biomarkers for clinical uses such as noninvasive early cancer diagnosis and evaluation of therapeutic efficacy. ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ By qualitatively or quantitatively analyzing disease‐related biomarkers of exosomes, the disease status can be detected. Without the engagement of nanotechnology, exosome detections relied on some traditional methods including western blot, ⁶⁹ enzyme‐linked immunosorbent assay, ⁷⁰ and enzyme‐assisted or enzyme‐free amplification‐dependent fluorescence assays. ⁷¹ , ⁷² The shortcomings of these methods are either low sensitivity, low specificity, or time‐consuming. For example, from one study, exosomes in supernatant from culture of at least 3.5–10 million cells were required for western blot analysis. ⁶⁹ The studies of using NPs for exosomes‐based clinic use aim to develop fast, cheap, and highly sensitive techniques for diagnosis of diseases like cancers, cardiovascular diseases, neurodegeneration, and metabolic diseases. Some laboratories develop different strategies to reach this aim and their works using real clinic samples show promises to transplant these strategies for clinical application (Table 2).

TABLE 2.

Examples of NPs‐based exosome detection

Type		Purification method	Substrate	Signal detection	Detection limit	References
Fluorescence	Solution‐based	Immunoaffinity capture	Cholesterol‐modified magnetic beads	CuO NPs	48 k/μl	[73]
	Microfluidic‐based	Immunoaffinity capture	Graphene oxide/polydopamine nano‐interface	FITC‐labeled CD81	1 k/μl	[63]
	Paper‐based	Ultracentrifugate	Paper‐supported aptasensor	Gold nanorod modified with DNA	1.1 k/μl	[74]
Electrochemistry	Conventional electrode based	Magnetic bead separation	Glassy carbon	Dissolved CdSe quantum dots	100/μl	[75]
	Screen‐printed electrode‐based	Simple centrifugation	Nanostructured gold	AgNPs or CuNPs	50/sensor	[76]
	Micropatterned electrode‐based	Ultrafiltration	Gold NPs	Methylene Blue	1 million /ml	[77]
Colorimetry	Paper‐based lateral flow	Ultracentrifugation	Nitrocellulose membrane	Anti‐CD63 labeled with AuNPs	0.8 million/ml	[78]
Colorimetry	Solution‐based	Magnetic bead	Magnetic bead‐labeled CD63 aptamer	Ag@Au	160/μl	[79]
Resonance	μNMR	Ultracentrifugation	Magnetic NPs	N/A	10⁴/ml	[80]
	SPR	Microfluidic device	Nanoporous gold nanocluster	Antibody AuNPs	1000/ml	[81]
	LSPR	Ultracentrifuge	Gold nanoislands	N/A	0.194 μg/ml	[82]
	SERS	Immunoaffinity capture	Glass solid	Ag@Au	540/ml	[83]
	SERS	Magnetic bead	Magnetic substrate	AuNPs@SERS reporter	32–200/ml	[56]

Open in a new tab

Abbreviations: AuNPs, gold nanospheres; CuNPs, coppernanospheres; FITC, fluorescein isothiocyanate; LRSPP, long‐range surface plasmon polariton; LSPR, local surface plasmon resonance; SERS, surface‐enhanced Raman scattering nanorods; SPR, surface plasmon resonance.

Different strategies for quantitative analysis of exosomes have been developed. When used for quantitatively testing exosomes in liquid biopsy, some surface markers on exosomes are usually targeted. ⁸⁴ In this strategy, the targeted surface markers in exosomes can be classified into two categories. The first one belongs to the group of intrinsic molecules. These molecules include CD63, Alix, and HSP70 which are common to varieties of exosomes and are usually used to identify the isolated crude products. ⁸⁵ Another group is composed of specific proteins closely correlated with the occurrence or development of diseases, such as protein PD‐L1 in melanoma cell‐derived exosomes and EpCAM in exosomes from epithelial malignant tumors like lung and colon cancers. ⁸⁶ , ⁸⁷ , ⁸⁸ These markers are valuable for clinical diagnosis. To target the disease‐correlated markers, either their respective antibodies or oligo DNA named aptamers are used. ⁸⁹ , ⁹⁰ Compared to antibodies, the advantages of aptamer applications, like lower cost and ease of modifications, are attracting more interests in recent years. ⁹¹ To quantitatively monitor in vivo distribution, exosomes can also be labeled by internalizing contrast agents. An example is that AuNPs were in vitro encapsulated inside exosomes. After administration into animals, both distribution and accumulation quantity in tissues can be monitored by in vivo CT imaging. ⁹² Some other information molecules like microRNAs that reside in exosome compartment are also reported as target for quantitative detection aim. ²⁴

3.1. Fluorescence‐based detection

Because of their excellent properties like size‐regulable emission spectra and stronger photoluminescence performance compared to conventional organic fluorophores, quantum dots (QDs) are ideal fluorophores for fluorescent detection of exosomes. In one study, cadmium selenide (CdSe) QDs conjugated with IL13 bound exosomes released from glioma stem cells which express receptor IL13Rα2. ⁹³ Copper ions dissolved from CuO NPs can form copper NPs (CuNPs) under reduction condition, and the latter emit fluorescence in an intensity proportional to the concentration of copper ions. This mechanism was reported for exosome quantification. ⁷³

QDs are also used for quantitative exosome analysis based on a mechanism known as Förster resonance energy transfer (FRET). In one study, the fluorescence of QDs on the surface of Fe₃O₄ NPs was designed to be quenched by AuNPs, which are drawn to proximity by pairing of aptamers conjugated to them (Figure 2). When incubated with exosomes, competitive binding of exosome surface markers with the aptamers expelled AuNPs, resulting in an exosome concentration‐dependent restoration of QDs fluorescence. When lung cancer epithelial marker EpCAM was targeted by aptamer, this system can detect as low as 13 exosome particles/ml sample with 100% accuracy, showing great clinical application potential. ⁹⁴ In this strategy, three different NPs were used for different applications. Fe₃O₄ NPs were used as both a platform carrier and exosome isolation tool, while QDs and AuNPs formed a fluorophore‐quencher pair.

Exosome detection based on Förster resonance energy transfer (FRET) by the fluorophore‐quencher pair of quantum dots (QDs) and AuNPs. (a) Schematic illustration of a FRET‐based exosome detection strategy. (b) The fluorescence of QD on Fe₃O₄ nanoparticles (NPs) (Fe₃O₄@QD@Apt, green line) is quenched by the formation of complex directed by a complementary DNA conjugated on AuNPs (Fe₃O₄@Au, black line). (c) Fluorescence intensity increase based on FRET ON. (d) The fluorescence intensity recovery occurs in AptCD63‐ and AptEpCAM‐containing systems with the addition of exosomes. (e) Detection of the CD63 and EpCAM expression on serum‐derived exosomes using Fe₃O₄@Au systems functionalized with AptCD63 or AptEpCAM (image reprinted with permission from Reference [94])

To realize these applications, exosomes were labeled with QDs by different approaches. Like other types of extracellular vesicles, exosome surface is rich in primary amines, which has been used to engage amine‐reactive NHS‐ester reaction for QDs labeling. ⁹⁵ Antibodies and aptamers were also utilized to conjugate QDs to exosome surface. ⁹⁶ , ⁹⁷ , ⁹⁸

Two‐dimensional NPs have a structure of single atomic layer and incline to form π‐π electron stacking interactions with biological and chemical molecules like DNA, proteins and fluorescent molecules, thus possessing a high distance‐dependent fluorescence quenching capability. ⁹⁹ , ¹⁰⁰ In recent years, different types of 2D NPs have raised great interests for their potential applications as a nanoquencher in FRET‐based biosensor platform. By using graphene oxide, EpCAM‐positive exosomes derived from colorectal cancer cells were quantitatively determined in a fast manner (~30 min) although in a medium sensitivity (2.1 × 10⁴ particles/μl). ¹⁰¹ By using Ti₃C₂ MXenes nanosheet, PSMA (prostate‐specific membrane antigen) and TPK‐7 (a marker of several cancer types) positive exosomes were measured in a sensitivity 1000 times higher than the traditional ELISA method. ¹⁰²

Some NPs are also used in a similar technology named luminescence resonance energy transfer (LRET) for exosome quantification. ⁷⁴ In this strategy, upconversion and AuNPs are used and a sensitivity of 1000 particles/μl was reached by using CD63 as a test aptamer.

3.2. Electrochemistry‐based detection

Oxidation potentials and degradability of metal NPs make them useful in electrochemical quantification of exosomes. When the oxidation potentials of two metal NPs are sufficiently differentiated, multiple markers on exosome surface can be detected simultaneously. For example, in order to simultaneously test PSA and EpCAM level in serum exosomes derived from prostate cancer patients, silver NPs (AgNPs) and CuNPs are used because their oxidation potentials fall in the potential window of gold electrodes and are well separated. When a linear sweep voltammetry is applied, they are oxidized under different voltages in an intensity proportional to the quantity of their surface markers. ⁷⁶ CdSe QDs functionalized with the HER‐2 and FAM134B antibodies, which target respective exosome markers of breast and colon cancer cells, bind with exosomes in a proportion to their amount. The bound CdSe QDs will dissociate Cd²⁺ under acidic condition which can be quantified by anodic stripping voltammetry. ⁷⁵ Besides, DNA nanotetrahedron‐modified electrode employed aptamer to capture more exosomes and, therefore, enhanced the detection sensitivity. ¹⁰³

3.3. Colorimetry‐based detection

Two intrinsic properties of NPs make them applicable in colorimetry‐based exosome quantification. First, some NPs, like AuNPs, show different colors dependent on their aggregation state. Second, NPs with peroxidase activity can catalyze colorimetric reactions. ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ AuNPs coated by aptamers are well dispersed in high salt solution. When exosomes are added, the complex of aptamer‐AuNPs are replaced by aptamer‐exosome, resulting in AuNP aggregation and a red to blue color change, which can be monitored by absorption spectroscopy. ¹⁰⁷ By this mechanism, both ubiquitous and exosome‐specific markers can be accurately tested in a time scale of minutes.

Binding of other molecules can change the intrinsic enzymatic activity of NPs, a property which has been exploited for exosome quantification. For example, graphitic carbon nitride nanosheets bound with single‐strand DNA (aptamers) shows a four times higher peroxidase activity compared to naked ones, and the catalytic activity is proportionally decayed when exosomes carrying the respective marker molecules competitively bind and strip the aptamers from the nanosheets. The change in the catalytic activity can be quantified by colorimetric measurement of H₂O₂‐mediated TMB oxidation. ¹⁰⁵

3.4. Resonance‐based detection

Optical techniques based on light‐matter interactions have been developed for extracellular vesicles including exosomes analysis. Compared to the electrochemical methods, optical detection has higher reproducibility. These optical techniques include surface plasmon resonance (SPR), local surface plasmon resonance (LSPR), long‐range surface plasmon polariton (LRSPP), and surface‐enhanced Raman scattering (SERS). AuNPs, including gold nanospheres and nanorods (AuNRs) are the most used NPs because they resonantly couple with the surface plasmas of the biosensor chip, thus acting as a signal amplifier. ⁸¹ , ⁸² Different groups have reported their studies using this strategy to analyze exosomes derived from lung cancer and hepatic carcinoma patients. ⁸¹ , ¹⁰⁸ , ¹⁰⁹ According to these studies, a limit of detection as low as 500 exosomes/μl sample can be achieved, which is much lower compared to that obtained by other protocols like colorimetry‐ and fluorescence‐based ones. This mechanism was also applied for in vivo exosome imaging. ⁹² The higher sensitivity of AuNPs‐based plasmon biosensor attributes to the fact that a high density of local AuNPs on exosomes can be achieved by different methods. First, AuNPs conjugated with different antibodies/aptamers can be used to recognize different surface ligands simultaneously. Second, antibodies/aptamers conjugated AuNPs can be further modified by reductants (e.g., polydopamine) in order to in situ produce AuNPs from HAuCl₄, which will further amplify plasmon resonance signals (Figure 3). ¹¹⁰

A surface plasmon resonance (SPR) strategy for exosome detection based on a three‐step process. In step 1, aptamer 1 is linked to a DNA tetrahedron probes (DTPs), which are supported on an Au film to prevent gold deposition on the surface. In step 2, exosomes are captured by the aptamer 1 which is complementary to DTPs, and aptamer 2 (here it is CD63)—linked Au@PDA NPs recognize and bind exosomes. In step 3, HAuCl₄ is introduced and in situ reduced to AuNPs by polydopamine coated on the AuNP surface. The reduction results in a further enhanced SPR signal (image reprinted with permission from Reference [110])

4. EXOSOMES FOR NPS‐BASED DISEASE THERAPY

The requirements for an ideal chemotherapy strategy, such as targeted drug delivery and high therapeutic efficacy, inspire people to hybrid NPs and exosomes in a single system. In this hybrid, exosomes usually function as natural nanocarriers with incomparable advantages like higher biocompatibility, extended blood half‐life, and capability of translocation through physical barriers and target‐homing. ¹ Meanwhile, NPs per se may act as a therapeutic reagent or function as drug deliverers. The complementary properties of exosomes and NPs can be well taken advantages of in this system. Exosomes as natural drug delivery carriers have limitations like low payload capability, which is often blamed to be the reason of low therapeutic efficiency after in vivo administration. ¹¹¹ This limitation can be overcome by NPs, which can load significant amount of drugs, protect them from degradation, and realize controllable drug release by proper chemical modifications. ¹¹² Although the targeting capability of NPs can be entitled by conjugation of targeting ligands on NP surface, it is not uncommon to find that the targeting ligands deteriorate the stability and change in vivo distribution of NPs after administration by a mechanism involving corona formation on a NP surface. ¹¹² The use of exosomes as targeting moieties will help avoid such problems. The NPs‐exosome hybrids showed considerably increased therapeutic efficiency in different biomedical applications (Table 3).

TABLE 3.

Examples of NPs‐exosome hybrid for biomedical applications

NPs	Exosome‐origins	Engineering methods	Cell/animal models	Applications	Efficiency	References
PEGylated spherical HGNs, 45 nm	B16‐F10 cells	HGNs stimulated exosome release by incubation with cells	B16‐F10 cells	NIR‐based cancer hyperthermia	Two times higher temperature than that in control after 30 min	[37]
PMA‐coated Au‐BSA@Ce6 NPs, 6–9 nm	Gastric cancer patients' urine	Exos‐PMA/Au‐BSA@Ce6 by electroporation with NPs and exosomes	MGC‐803 (a human gastric cancer cell line) tumor‐bearing mice	Cancer‐targeted photodynamic therapy	Deeper permeability and superior retention than exosome absence group; 20 days life span extension than PBS group.	[113]
Black phosphorus QDs, 1–3 nm	Serum from hyperthermia‐treated mice	Sonication of NPs/exosomes mixture	LLC/RAW264.7/ 4 T1 cells; Balb/c nude mice bearing LLC‐induced lung cancer	Anticancer photo‐nanovaccine	Long‐term PTT; higher tumor temperature and targeting efficacy; higher immune system activation efficiency.	[114]
TAT modified 2D vanadium carbide (V₂C) QDs, nanosheet, 16 × 2.5 nm	MCF‐7 cells	Exos‐RGD by cell culture; V₂C ‐TAT@Ex‐RGD by electroporation	MCF‐7/NHDF/A549 cells; MCF‐7 tumor‐bearing BALB/c nude mice	Nucleus‐targeting low‐temperature photothermal therapy and fluorescence imaging, PAI and MRI multi‐model tumor imaging	Higher photothermal conversion efficiency than other nano‐PTAs; 2.84 times stronger nucleus targeting ability than V2C‐TAT; 3.73‐fold higher MR signal than control; higher tumor accumulation and negligible side effects	[115]
MIL‐88A, an iron‐based MOFs, roundish, 52 nm	Hela cells	Exos‐MIL‐88A by lipid fusion with NPs and exosomes	Hela cells	Drug delivery	3 times higher IC50 compared with free SBHA	[116]
Spheric SPIONs	Raw264.7 cells	RGE‐Exo‐SPION/Cur formed by electroporation and click chemistry	Bel‐7404/ U251 cells; tumor‐bearing mice	Imaging and therapy of glioma	Longer survival than control groups	[117]
Dox loaded spheric PSiNPs with11 nm pore	Bel7402 cells	DOX@Exos‐PSiNPs by NPs incubation with cells	H22 CSCs tumor spheroids; H22 tumor‐bearing mice	Drug delivery	2 times targeted in vivo and in vitro tumor accumulation; 3.2 times DOX retention; higher tumor growth inhibition; 40 days longer survival time	[44]
Pd nanosheet, 1.4 nm in thickness	A549 cells	In situ synthesis of Pd‐Exos from K₂PdCl₄	A549/U87/ RAW246.7 cells	Anticancer prodrug delivery	Targeted cancer therapy	[118]

Open in a new tab

Abbreviations: BSA, bovine serum albumin; Cur, curcumin; CSC, cancer stem cells; Dox, doxorubicin; HGNs, hollow gold nanoparticles; exos: exosomes; NIR, near‐infrared; NP, nanoparticle; PMA, amphiphilic polymer; PSiNPs, porous silicon nanoparticles; PTT, photothermal therapy; QDs, quantum dots; RGE: RGERPPR peptide; SBHA, suberohydroxamic acid; SPIONs, superparamagnetic iron oxide nanoparticles; TAT, TAT peptide (for nucleus targeting).

Two different approaches have been reported to prepare NPs‐exosome hybrids. In the first approach, NPs are added to the cell culture to stimulate cellular endocytosis, by which NPs are loaded inside exosomes. In the second approach, NPs are encapsulated into the isolated exosomes in tubes by various physical methods like electroporation or freeze–thaw cycles, or by in situ synthesis of NPs starting from ions. A reported in situ synthesis example is the delivery of catalyst Pd nanocrystals starting from Pd ions. ¹¹⁹

4.1. In tumor therapy

When used in exosome‐mediated tumor therapy, NPs are playing different roles in the NPs‐exosome hybrids. First, they per se may act as therapeutic reagents. Hollow AuNPs can significantly convert near‐infrared light into heat and thus are often used in cancer photothermal therapy. ¹²⁰ When they were encapsulated into exosomes by an endogenous method and were carried into melanoma cells, they efficiently increased the temperature of cells in culture under near‐infrared laser irritation. ³⁷ This photothermal effect was also realized by hollow AuNPs delivered by exosomes in mesenchymal stem cells. ¹²¹ Noticeably, because of their homing selection, exosomes derived from mesenchymal stem cells only enter mesenchymal cells but no other cell types in culture. Another type of NPs, black phosphorus (BP) nanosheets were also reported in an exosome‐mediated tumor photothermal therapy. In this study, after intravenous injection into mice, BP carrying exosomes were accumulated in tumors because of their homing selection, ¹²² and application of near‐infrared laser irritation efficiently produced local heat and ablated tumors (Figure 4). ¹¹⁴

In vivo photothermal performance of a hybrid of black phosphorus quantum dots (BPQDs) encapsulated in exosomes (hEX@BP) in lung cancer mouse models. (a) Graphic illustration of hybrid construction. Exosomes (hEX) are extracted from the plasma of hyperthermia‐treated tumor‐bearing mice, and are used to encapsulate BPQDs by an ultrasonic method. (b) Left: Live imaging of mice with a lung xenograft tumor injected with DiR‐labeled hEX and hEX@BP. Middle: Ex vivo images of lung tumor and whole‐body organs (heart, liver, spleen, lung, and kidney). Right: Fluorescent frozen section of tumors (bar: 50 μm) from different‐treatment mouse groups. hEXs are stained with DiR (red) and DNA are stained with DAPI (blue). (c) Smaller tumor size in NIR radiation treated mice (Image reprinted with permission from Reference [114])

Second, NPs work as a drug deliverer. In one study, Dox/siNPs‐encapsulated exosomes were successfully produced by a pre‐loading approach, in which doxorubicin loading porous silicon NPs were exposed to cultured hepatocarcinoma cells and they were released by cells in the form of Dox/siNP‐loaded exosomes. When administrated by intravenous injection to mice bearing hepatocarcinoma tumors, the exosomes accumulated in a high efficiency in tumors and doxorubicin were released from NPs killing both bulk tumor cells and cancer stem cells. ⁴⁴

The targeting capability of exosomes can be endowed by genetically engineering of parental cells. For example, by fusing neuron‐specific peptide gene to Lamp2b (a ubiquitous exosome membrane protein) in dendritic cells, a neuron‐targeting exosome pool was achieved. ¹²³ In another study, an Arg‐Gly‐Asp (RGD) peptide, which specifically recognizes the integrin α_vβ₃ of tumor cells and vasculatures, was incubated with cancer cell line to generate RGD expressing exosomes (Exo‐RGD). QDs coated with TAT peptide (for nucleus targeting) were encapsulated into Exo‐RGD by electroporation. When applied to animal models, this theragnostic platform showed good biocompatibility and long circulation time, and targeted cancer cells with a high transfection efficacy. ¹²⁴

In BALB/c mice, the exposure to magnetic NPs generated exosomes in the alveolar region, which consequently stimulated T‐cell activation. ¹²⁵ This provides a mechanistic explanation for toxicity caused by NPs administration, but meanwhile, it also implicated the possibility of using this strategy for tumor nano‐vaccine development. ¹¹⁴

4.2. In therapy for other diseases

The combination of NPs and exosomes was also exploited for treatment of other diseases. In a notable study, core‐shell magnetic NPs were conjugated with dual antibodies, with one (CD63) against antigens on exosome surface and the other (myosin‐light‐chain, MLC) targeting recipient cells (the injured cardiomyocytes). These dual functionalized NPs were used as vesicle shuttle of capturing and delivering endogenous exosomes to the targeted area, where exosomes were selectively released from NPs to generate the therapeutic effect for myocardial infarction, including promoted angiogenesis, reduced infarct size, and improved left‐ventricle ejection fraction in animal model. ¹²⁶ Because the selection of targeted antigens on exosome surface can be further optimized, the specificity and efficiency to deliver exosomes still has room of improvement. Thus, this approach has great promises of clinic applications for myocardial infarction treatment. Studies have shown that exosomes containing pro‐coagulation and pro‐inflammatory factors contribute to thrombosis in myocardial infarction. ¹²⁷ This finding justifies a strategy for infarction treatment, in which exosomes containing these factors can be recognized and tethered by NPs with conjugation of appropriate antibodies, thus reducing their accumulation in the infarct site and ameliorating infarct size. The same strategy was also used for cerebral disease treatment ⁹² , ¹²⁸ and monitoring and improving fetal health. ¹²⁹ In both applications, the capability of exosomes to breakdown physiological barriers (blood–brain barrier [BBB] ¹²⁹ and placenta barrier ¹³⁰ ) was taken use of. Drugs carried by this system can be more efficiently delivered to targeted sites to realize the maximal therapy efficacy. ¹³¹ , ¹³² , ¹³³ Moreover, therapeutic properties of NPs, like the photothermal effect, capability to activate immunity of targeted cells, and long retention time in tumors, can synergize drug therapy efficiency (Figure 5 ). ¹¹³ , ¹²⁶ , ¹³⁴

Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody‐conjugated magnetic nanoparticles (NPs). The magnetic NPs, designated as GMNP_EC, consist of a Fe₃O₄ core and a silica shell that is decorated with poly (ethylene glycol) conjugated to two antibodies respectively recognizing CD63 and myosin‐light‐chain (MLC) via hydrazone bonds. While anti‐CD63 antibodies capture and attach to endogenous circulating exosomes, anti‐MLC antibodies lead exosomes to target MLC on the damaged cardiomyocytes when GMNP_EC are enriched in the infarct area by the application of a local magnetic field. In the infarct area, exosomes are released from GMNP_EC due to the acidosis‐induced cleavage of hydrazone bonds. In animal models of myocardial infarction, the accumulation of CD63‐expressing exosomes in infarcted tissue leads to reductions in infarct size as well as improves left‐ventricle ejection fraction and angiogenesis (Image reprinted with permission from Reference [126])

5. CONCLUSIONS AND PERSPECTIVES

Nanotechnology is aiding exosome studies and applications in medicine in different ways. Besides improving purification efficiency and detection sensitivity of those current technologies, the use of various NPs as theragnostic carriers significantly enhance the drug loading capability of exosomes in disease therapy. Meanwhile, the homing selection property makes exosomes ideal targeting moieties in NPs‐based drug delivery system and help to overcome limitations caused by conjugation of targeting molecules on NPs' surface. Even though big progress has been achieved in recent years, till today there is no approval for commercial diagnostic kits or drugs based on NPs‐exosome hybrids. This is because some major obstacles confronting clinical applications of NPs‐exosome hybrids. For exosome detection in liquid biopsy, most of currently developed technologies are on the stage of proof‐of‐concept and successful detection is dependent on the purification of exosome. Although showing clinically satisfactory sensitivity and specificity, the steps before the detection, including operation of sampling, transportation, and purification, are yet to be standardized to ensure test repeatability, reproducibility, and minimal false negative ratio. Reliable and specific markers for tumor diagnosis and prognosis evaluation are still lacking. When used for in vivo applications like drug delivery, the limitations of the NPs‐exosome hybrids include the concerns raised by the potential toxicity of various artificial NPs. Moreover, by current approaches, it is still difficult to produce sufficient exosomes with constant quality and controllable properties like composition uniformity. The current endeavors of researchers are largely focusing on these issues and the accumulation of knowledge in NPs safety studies and exosome biology is promising to fill these gaps in future.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

Yabin Wang: Writing – review and editing (equal). Bing Yan: Project administration (lead); writing – review and editing (supporting).

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1002/btm2.10269.

ACKNOWLEDGMENT

This research was funded by the Foundation of State Key Laboratory of Biobased Material and Green Papermaking (No. 23190433), Qilu University of Technology, Shandong Academy of Sciences and the Chinese National Natural Science Funds. It was also funded by the National Natural Science Foundation of China (No. 22036002) and the introduced innovative R&D team project under the “The Pearl River Talent Recruitment Program” of Guangdong Province (2019ZT08L387).

Wang Y, Wang W, Kong F, et al. Tango of dual nanoparticles: Interplays between exosomes and nanomedicine. Bioeng Transl Med. 2022;7(2):e10269. doi: 10.1002/btm2.10269

Yabin Wang and Wenzhen Wang contributed equally to this study.

Funding information The Foundation of State Key Laboratory of Biobased Material and Green Papermaking, Grant/Award Number: 23190433; the National Natural Science Foundation of China, Grant/Award Number: 22036002; The Pearl River Talent Recruitment Program of Guangdong Province, Grant/Award Number: 2019ZT08L387; National Natural Science Foundation of China; Shandong Academy of Sciences

Contributor Information

Yi Zhang, Email: yz1154@cinj.rutgers.edu.

Bing Yan, Email: drbingyan@yahoo.com.

DATA AVAILABILITY STATEMENT

There are no supplementary data available for this article.

REFERENCES

1. van de Vlekkert D, Demmers J, Nguyen X‐X, Campos Y, Machado E, Annunziata I, Hu H, Gomero E, Qiu X, Bongiovanni A, Feghali‐Bostwick CA, d'Azzo A, Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis. Sci Adv 2019; 5(7): eaav3270. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Jakobsen KR, Paulsen BS, Bæk R, Varming K, Sorensen BS, Jørgensen MM, Exosomal proteins as potential diagnostic markers in advanced non‐small cell lung carcinoma. J Extracell Vesicles. 2015; 4(1): 26659. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Wang Z, Li F, Rufo J, Chen C, Yang S, Li L, Zhang J, Cheng J, Kim Y, Wu M, Abemayor E, Tu M, Chia D, Spruce R, Batis N, Mehanna H, Wong DTW, Huang TJ, Acoustofluidic salivary exosome isolation: a liquid biopsy compatible approach for human papillomavirus‐associated oropharyngeal cancer detection. J Mol Diagn 2020; 22(1): 50–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Jin X, Chen Y, Chen H, Fei S., Chen D., Cai X., Liu L., Lin B., Su H., Zhao L., Su M., Pan H., Shen L., Xie D., Xie C., Evaluation of tumor‐derived Exosomal miRNA as potential diagnostic biomarkers for early‐stage non‐small cell lung cancer using next‐generation sequencing. Clin Cancer Res 2017; 23(17): 5311–5319. [DOI] [PubMed] [Google Scholar]
5. Kalluri R, LeBleu VS, The biology, function, and biomedical applications of exosomes. Science 2020; 367(6478): eaau6977. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D, Exosome‐mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression. Signal Transduct Target Ther 2020; 5(1): 242. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Kim DH, Kothandan VK, Kim HW, Kim KS, Kim JY, Cho HJ, Lee YK, Lee DE, Hwang SR, Noninvasive assessment of exosome pharmacokinetics in vivo: a review. Pharmaceutics 2019; 11(12): 649. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Jesus S, Schmutz M, Som C, Borchard G., Wick P., Borges O., Hazard assessment of polymeric Nanobiomaterials for drug delivery: what can we learn from literature so far. Front Bioeng Biotechnol 2019; 7: 261. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Men Y, Yelick J, Jin S, Tian Y, Chiang MSR, Higashimori H, Brown E, Jarvis R, Yang Y, Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS. Nat Commun 2019; 10(1): 4136. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Li W, Liu Y, Zhang P, Tang Y, Zhou M, Jiang W, Zhang X, Wu G, Zhou Y, Tissue‐engineered bone immobilized with human adipose stem cells‐derived exosomes promotes bone regeneration. ACS Appl Mater Interfaces 2018; 10(6): 5240–5254. [DOI] [PubMed] [Google Scholar]
11. Zhang S, Teo KYW, Chuah SJ, Lai RC, Lim SK, Toh WS, MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials 2019; 200: 35–47. [DOI] [PubMed] [Google Scholar]
12. Liu X, Yang Y, Li Y, Niu X., Zhao B., Wang Y., Bao C., Xie Z., Lin Q., Zhu L., Integration of stem cell‐derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale 2017; 9(13): 4430–4438. [DOI] [PubMed] [Google Scholar]
13. Tian Y, Gong M, Hu Y, Liu H, Zhang W, Zhang M, Hu X, Aubert D, Zhu S, Wu L, Yan X, Quality and efficiency assessment of six extracellular vesicle isolation methods by nano‐flow cytometry. J Extracell Vesicles. 2020; 9(1): 1697028. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Dong L, Zieren RC, Horie K, Kim CJ, Mallick E, Jing Y, Feng M, Kuczler MD, Green J, Amend SR, Witwer KW, de Reijke TM, Cho YK, Pienta KJ, Xue W, Comprehensive evaluation of methods for small extracellular vesicles separation from human plasma, urine and cell culture medium. J Extracell Vesicles 2020; 10(2): e12044. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Veerman RE, Teeuwen L, Czarnewski P, Güclüler Akpinar G, Sandberg A, Cao X, Pernemalm M, Orre LM, Gabrielsson S, Eldh M, Molecular evaluation of five different isolation methods for extracellular vesicles reveals different clinical applicability and subcellular origin. J Extracell Vesicles. 2021; 10(9): e12128. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal‐Bengtson B, Dingli F, Loew D, Tkach M, Théry C, Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 2016; 113(8): E968‐977. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Luan X, Sansanaphongpricha K, Myers I, Chen H, Yuan H, Sun D, Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin 2017; 38(6): 754–763. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. de Jong OG, Kooijmans SAA, Murphy DE, Jiang L, Evers MJW, Sluijter JPG, Vader P, Schiffelers RM, Drug delivery with extracellular vesicles: from imagination to innovation. Acc Chem Res 2019; 52(7): 1761–1770. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Chen G, Roy I, Yang C, Prasad PN, Nanochemistry and nanomedicine for nanoparticle‐based diagnostics and therapy. Chem Rev 2016; 116(5): 2826–2885. [DOI] [PubMed] [Google Scholar]
20. Pelaz B, Alexiou C, Alvarez‐Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WCW, Chen C, Chen X, Chen X, Cheng Z, Cui D, du J, Dullin C, Escudero A, Feliu N, Gao M, George M, Gogotsi Y, Grünweller A, Gu Z, Halas NJ, Hampp N, Hartmann RK, Hersam MC, Hunziker P, Jian J, Jiang X, Jungebluth P, Kadhiresan P, Kataoka K, Khademhosseini A, Kopeček J, Kotov NA, Krug HF, Lee DS, Lehr CM, Leong KW, Liang XJ, Ling Lim M, Liz‐Marzán LM, Ma X, Macchiarini P, Meng H, Möhwald H, Mulvaney P, Nel AE, Nie S, Nordlander P, Okano T, Oliveira J, Park TH, Penner RM, Prato M, Puntes V, Rotello VM, Samarakoon A, Schaak RE, Shen Y, Sjöqvist S, Skirtach AG, Soliman MG, Stevens MM, Sung HW, Tang BZ, Tietze R, Udugama BN, VanEpps JS, Weil T, Weiss PS, Willner I, Wu Y, Yang L, Yue Z, Zhang Q, Zhang Q, Zhang XE, Zhao Y, Zhou X, Parak WJ, Diverse applications of nanomedicine. ACS Nano 2017; 11(3): 2313–2381. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Zhang H, Wang Z, Zhang Q, Wang F, Liu Y, Ti3C2 MXenes nanosheets catalyzed highly efficient electrogenerated chemiluminescence biosensor for the detection of exosomes. Biosens Bioelectron 2019; 124‐125: 184–190. [DOI] [PubMed] [Google Scholar]
22. Han J, Zhang L, Cui M, Su Y, He Y, Rapid and accurate detection of lymph node metastases enabled through fluorescent silicon nanoparticles‐based exosome probes. Anal Chem 2021; 93(29): 10122–10131. [DOI] [PubMed] [Google Scholar]
23. Wang J, Chen P, Dong Y, Xie H, Wang Y, Soto F, Ma P, Feng X, du W, Liu BF, Designer exosomes enabling tumor targeted efficient chemo/gene/photothermal therapy. Biomaterials 2021; 276: 121056. [DOI] [PubMed] [Google Scholar]
24. Zhao J, Liu C, Li Y, Ma Y, Deng J, Li L, Sun J, Thermophoretic detection of Exosomal microRNAs by Nanoflares. J Am Chem Soc 2020; 142(11): 4996–5001. [DOI] [PubMed] [Google Scholar]
25. Pan S, Zhang Y, Huang M, Deng Z, Zhang A, Pei L, Wang L, Zhao W, Ma L, Zhang Q, Cui D, Urinary exosomes‐based engineered nanovectors for homologously targeted chemo‐chemodynamic prostate cancer therapy via abrogating EGFR/AKT/NF‐kB/IkB signaling. Biomaterials 2021; 275: 120946. [DOI] [PubMed] [Google Scholar]
26. Xie X, Nie H, Zhou Y, Lian S, Mei H, Lu Y, Dong H, Li F, Li T, Li B, Wang J, Lin M, Wang C, Shao J, Gao Y, Chen J, Xie F, Jia L, Eliminating blood oncogenic exosomes into the small intestine with aptamer‐functionalized nanoparticles. Nat Commun 2019; 10(1): 5476. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Sheller‐Miller S, Choi K, Choi C, Cre‐reporter mouse model to determine exosome communication and function during pregnancy. Am J Obstet Gynecol 2019; 221(5): 502.e501‐502.e512. [DOI] [PubMed] [Google Scholar]
28. Mitchell MD, Peiris HN, Kobayashi M, Koh YQ, Duncombe G, Illanes SE, Rice GE, Salomon C, Placental exosomes in normal and complicated pregnancy. Am J Obstet Gynecol 2015; 213(4, Supplement): S173‐S181. [DOI] [PubMed] [Google Scholar]
29. Jiang N, Xiang L, He L, Yang G, Zheng J, Wang C, Zhang Y, Wang S, Zhou Y, Sheu TJ, Wu J, Chen K, Coelho PG, Tovar NM, Kim SH, Chen M, Zhou YH, Mao JJ, Exosomes mediate epithelium–mesenchyme crosstalk in organ development. ACS Nano 2017; 11(8): 7736–7746. [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Keller MD, Ching KL, Liang FX, Dhabaria A, Tam K, Ueberheide BM, Unutmaz D, Torres VJ, Cadwell K, Decoy exosomes provide protection against bacterial toxins. Nature 2020; 579(7798): 260–264. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Zhang T, Ma S, Lv J, Wang X, Afewerky HK, Li H, Lu Y, The emerging role of exosomes in Alzheimer's disease. Ageing Res Rev 2021; 68: 101321. [DOI] [PubMed] [Google Scholar]
32. Sun H, Wang C, Hu B, Gao X, Zou T, Luo Q, Chen M, Fu Y, Sheng Y, Zhang K, Zheng Y, Ren X, Yan S, Geng Y, Yang L, Dong Q, Qin L, Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3. Signal Transduct Target Ther 2021; 6(1): 187. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Guo H, Chitiprolu M, Roncevic L, Javalet C, Hemming FJ, Trung MT, Meng L, Latreille E, Tanese de Souza C, McCulloch D, Baldwin RM, Auer R, Côté J, Russell RC, Sadoul R, Gibbings D, Atg5 disassociates the V1V0‐ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy. Dev Cell 2017; 43(6): 716‐730.e717. [DOI] [PubMed] [Google Scholar]
34. Abdulrahman BA, Abdelaziz DH, Schatzl HM, Autophagy regulates exosomal release of prions in neuronal cells. J Biol Chem 2018; 293(23): 8956–8968. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Latifkar A, Ling L, Hingorani A, Johansen E, Clement A, Zhang X, Hartman J, Fischbach C, Lin H, Cerione RA, Antonyak MA, Loss of Sirtuin 1 alters the Secretome of breast cancer cells by impairing lysosomal integrity. Dev Cell 2019; 49(3): 393‐408.e397. [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Hao F, Ku T, Yang X Ku T, Yang X, Liu QS, Zhao X, Faiola F, Zhou Q, Jiang G, Gold nanoparticles disturb small extracellular vesicle attributes of mouse embryonic stem cells. Nanoscale 2020; 12, 15631, 15637. [DOI] [PubMed] [Google Scholar]
37. Sancho‐Albero M, Encabo‐Berzosa MdM, Beltrán‐Visiedo M, et al., Efficient encapsulation of theranostic nanoparticles in cell‐derived exosomes: leveraging the exosomal biogenesis pathway to obtain hollow gold nanoparticle‐hybrids. Nanoscale 2019; 11(40): 18825–18836. [DOI] [PubMed] [Google Scholar]
38. Al‐Nedawi K, Meehan B, Micallef J, et al., Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10(5): 619–624. [DOI] [PubMed] [Google Scholar]
39. Nawaz M, Camussi G, Valadi H, et al., The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nat Rev Nephrol 2014; 11(12): 688–701. [DOI] [PubMed] [Google Scholar]
40. Roma‐Rodrigues C, Pereira F, Alves de Matos AP, Fernandes M, Baptista PV, Fernandes AR, Smuggling gold nanoparticles across cell types—a new role for exosomes in gene silencing. Nanomed Nanotech Biol Med. 2017; 13(4): 1389–1398. [DOI] [PubMed] [Google Scholar]
41. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, Nilsson J, Lötvall J, Kim YK, Gho YS, Bioinspired exosome‐mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 2013; 7(9): 7698–7710. [DOI] [PubMed] [Google Scholar]
42. Wan Y, Wang L, Zhu C, Zheng Q, Wang G, Tong J, Fang Y, Xia Y, Cheng G, He X, Zheng SY, Aptamer‐conjugated extracellular nanovesicles for targeted drug delivery. Cancer Res 2018; 78(3): 798–808. [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Gurunathan S, Kang M‐H, Jeyaraj M, Kim JH, Platinum nanoparticles enhance exosome release in human lung epithelial adenocarcinoma cancer cells (A549): oxidative stress and the ceramide pathway are key players. Int J Nanomedicine 2021; 16: 515–538. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Yong T, Zhang X, Bie N, Zhang H, Zhang X, Li F, Hakeem A, Hu J, Gan L, Santos HA, Yang X, Tumor exosome‐based nanoparticles are efficient drug carriers for chemotherapy. Nat Commun 2019; 10(1): 3838. [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Park DJ, Yun WS, Kim WC, Park JE, Lee SH, Ha S, Choi JS, Key J, Seo YJ, Improvement of stem cell‐derived exosome release efficiency by surface‐modified nanoparticles. J Nanobiotechnol. 2020; 18(1): 178. [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Vella LJ, Scicluna BJ, Cheng L, Bawden EG, Masters CL, Ang CS, Willamson N, McLean C, Barnham KJ, Hill AF, A rigorous method to enrich for exosomes from brain tissue. J Extracell Vesicles. 2017; 6(1): 1348885. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ, Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863‐derived exosomes. Methods 2012; 56(2): 293–304. [DOI] [PubMed] [Google Scholar]
48. Lobb R, Möller A, Size exclusion chromatography: a simple and reliable method for exosome purification. Methods Mol Biol 2017; 1660: 105–110. [DOI] [PubMed] [Google Scholar]
49. Busatto S, Vilanilam G, Ticer T, Lin WL, Dickson D, Shapiro S, Bergese P, Wolfram J, Tangential flow filtration for highly efficient concentration of extracellular vesicles from large volumes of fluid. Cell 2018; 7(12): 273. [DOI] [PMC free article] [PubMed] [Google Scholar]
50. Rider MA, Hurwitz SN, Meckes DG, Jr. , ExtraPEG: a polyethylene glycol‐based method for enrichment of extracellular vesicles. Sci Rep 2016; 6: 23978. [DOI] [PMC free article] [PubMed] [Google Scholar]
51. Chen C, Skog J, Hsu C‐H, Lessard RT, Balaj L, Wurdinger T, Carter BS, Breakefield XO, Toner M, Irimia D, Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 2010; 10(4): 505–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
52. Zhang W, Yu Z‐L, Wu M, Ren JG, Xia HF, Sa GL, Zhu JY, Pang DW, Zhao YF, Chen G, Magnetic and folate functionalization enables rapid isolation and enhanced tumor‐targeting of cell‐derived microvesicles. ACS Nano 2017; 11(1): 277–290. [DOI] [PubMed] [Google Scholar]
53. Pang Y, Shi J, Yang X, Wang C, Sun Z, Xiao R, Personalized detection of circling exosomal PD‐L1 based on Fe3O4@TiO2 isolation and SERS immunoassay. Biosens Bioelectron 2020; 148: 111800. [DOI] [PubMed] [Google Scholar]
54. Lim J, Choi M, Lee H, Kim YH, Han JY, Lee ES, Cho Y, Direct isolation and characterization of circulating exosomes from biological samples using magnetic nanowires. J Nanobiotechnol 2019; 17(1): 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Yang L, Han D, Zhan Q, Li X, Shan P, Hu Y, Ding H, Wang Y, Zhang L, Zhang Y, Xue S, Zhao J, Hou X, Wang Y, Li P, Yuan X, Qi H, Blood TfR+ exosomes separated by a pH‐responsive method deliver chemotherapeutics for tumor therapy. Theranostics. 2019; 9(25): 7680–7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
56. Wang Z, Zong S, Wang Y, Li N, Li L, Lu J, Wang Z, Chen B, Cui Y, Screening and multiple detection of cancer exosomes using an SERS‐based method. Nanoscale 2018; 10(19): 9053–9062. [DOI] [PubMed] [Google Scholar]
57. Jauregui R, Srinivasan S, Vojtech LN, Gammill HS, Chiu DT, Hladik F, Stayton PS, Lai JJ, Temperature‐responsive magnetic nanoparticles for enabling affinity separation of extracellular vesicles. ACS Appl Mater Interfaces 2018; 10(40): 33847–33856. [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Lee S‐K, Kim G‐S, Wu Y, Kim DJ, Lu Y, Kwak M, Han L, Hyung JH, Seol JK, Sander C, Gonzalez A, Li J, Fan R, Nanowire substrate‐based laser scanning cytometry for quantitation of circulating tumor cells. Nano Lett 2012; 12(6): 2697–2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
59. Lin S, Yu Z, Chen D, Wang Z, Miao J, Li Q, Zhang D, Song J, Cui D, Progress in microfluidics‐based exosome separation and detection Technologies for Diagnostic Applications. Small 2020; 16(9): e1903916. [DOI] [PubMed] [Google Scholar]
60. Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, Hochberg FH, Breakefield XO, Lee H, Weissleder R, Chip‐based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun 2015; 6(1): 6999. [DOI] [PMC free article] [PubMed] [Google Scholar]
61. Liu C, Guo J, Tian F, Yang N, Yan F, Ding Y, Wei JY, Hu G, Nie G, Sun J, Field‐free isolation of exosomes from extracellular vesicles by microfluidic viscoelastic flows. ACS Nano 2017; 11(7): 6968–6976. [DOI] [PubMed] [Google Scholar]
62. Wunsch BH, Smith JT, Gifford SM, Wang C, Brink M, Bruce RL, Austin RH, Stolovitzky G, Astier Y, Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol 2016; 11(11): 936–940. [DOI] [PubMed] [Google Scholar]
63. Zhang P, He M, Zeng Y, Ultrasensitive microfluidic analysis of circulating exosomes using a nanostructured graphene oxide/polydopamine coating. Lab Chip 2016; 16(16): 3033–3042. [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Helmke BP, Minerick AR, Designing a nano‐interface in a microfluidic chip to probe living cells: challenges and perspectives. Proc Natl Acad Sci U S A 2006; 103(17): 6419–6424. [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Chen IH, Xue L, Hsu CC, Paez JSP, Pan L, Andaluz H, Wendt MK, Iliuk AB, Zhu JK, Tao WA, Phosphoproteins in extracellular vesicles as candidate markers for breast cancer. Proc Natl Acad Sci U S A 2017; 114(12): 3175–3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Yuan L, Li JY, Exosomes in Parkinson's disease: current perspectives and future challenges. ACS Chem Nerosci 2019; 10(2): 964–972. [DOI] [PubMed] [Google Scholar]
67. Kranendonk ME, de Kleijn DP, Kalkhoven E, Kanhai DA, Uiterwaal CS, van der Graaf Y, Pasterkamp G, Visseren FL, SMART Study Group , Extracellular vesicle markers in relation to obesity and metabolic complications in patients with manifest cardiovascular disease. Cardiovasc Diabetol 2014; 13: 37. [DOI] [PMC free article] [PubMed] [Google Scholar]
68. Wu AY, Ueda K, Lai CP, Proteomic analysis of extracellular vesicles for cancer diagnostics. Proteomics 2019; 19(1–2): e1800162. [DOI] [PubMed] [Google Scholar]
69. Zhang H‐G, Liu C, Su K, Yu S, Zhang L, Zhang S, Wang J, Cao X, Grizzle W, Kimberly RP, A membrane form of TNF‐α presented by exosomes delays T cell activation‐induced cell death. J Immunol (Baltimore, Md): 1950. 2006; 176: 7385–7393. [DOI] [PubMed] [Google Scholar]
70. Logozzi M, De Milito A, Lugini L, et al., High levels of exosomes expressing CD63 and caveolin‐1 in plasma of melanoma patients. PLoS One 2009; 4(4): e5219. [DOI] [PMC free article] [PubMed] [Google Scholar]
71. Zhang DY, Seelig G, Dynamic DNA nanotechnology using strand‐displacement reactions. Nat Chem 2011; 3(2): 103–113. [DOI] [PubMed] [Google Scholar]
72. Wang X, Shang H, Ma C, Chen L, A fluorescence assay for exosome detection based on bivalent cholesterol anchor triggered target conversion and enzyme‐free signal amplification. Anal Chem 2021; 93(24): 8493–8500. [DOI] [PubMed] [Google Scholar]
73. He F, Wang J, Yin B‐C, Ye BC, Quantification of exosome based on a copper‐mediated signal amplification strategy. Anal Chem 2018; 90(13): 8072–8079. [DOI] [PubMed] [Google Scholar]
74. Chen X, Lan J, Liu Y, Li L, Yan L, Xia Y, Wu F, Li C, Li S, Chen J, A paper‐supported aptasensor based on upconversion luminescence resonance energy transfer for the accessible determination of exosomes. Biosens Bioelectron 2018; 102: 582–588. [DOI] [PubMed] [Google Scholar]
75. Boriachek K, Islam MN, Gopalan V, Lam AK, Nguyen NT, Shiddiky MJA, Quantum dot‐based sensitive detection of disease specific exosome in serum. Analyst 2017; 142(12): 2211–2219. [DOI] [PubMed] [Google Scholar]
76. Zhou Y‐G, Mohamadi RM, Poudineh M, Kermanshah L, Ahmed S, Safaei TS, Stojcic J, Nam RK, Sargent EH, Kelley SO, Interrogating circulating microsomes and exosomes using metal nanoparticles. Small 2016; 12(6): 727–732. [DOI] [PubMed] [Google Scholar]
77. Zhou Q, Rahimian A, Son K, Shin DS, Patel T, Revzin A, Development of an aptasensor for electrochemical detection of exosomes. Methods 2016; 97: 88–93. [DOI] [PubMed] [Google Scholar]
78. Oliveira‐Rodríguez M, López‐Cobo S, Reyburn HT, Costa‐García A, López‐Martín S, Yáñez‐Mó M, Cernuda‐Morollón E, Paschen A, Valés‐Gómez M, Blanco‐López MC, Development of a rapid lateral flow immunoassay test for detection of exosomes previously enriched from cell culture medium and body fluids. J Extracell Vesicles. 2016; 5(1): 31803. [DOI] [PMC free article] [PubMed] [Google Scholar]
79. Zhang Y, Wang D, Yue S, Lu Y, Yang C, Fang J, Xu Z, Sensitive multicolor visual detection of exosomes via dual signal amplification strategy of enzyme‐catalyzed metallization of Au Nanorods and hybridization chain reaction. ACS Sensors 2019; 4(12): 3210–3218. [DOI] [PubMed] [Google Scholar]
80. Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS, Hochberg FH, Breakefield XO, Weissleder R, Lee H, Protein typing of circulating microvesicles allows real‐time monitoring of glioblastoma therapy. Nat Med 2012; 18(12): 1835–1840. [DOI] [PMC free article] [PubMed] [Google Scholar]
81. Yang Q, Cheng L, Hu L, Lou D, Zhang T, Li J, Zhu Q, Liu F, An integrative microfluidic device for isolation and ultrasensitive detection of lung cancer‐specific exosomes from patient urine. Biosens Bioelectron 2020; 163: 112290. [DOI] [PubMed] [Google Scholar]
82. Thakur A, Qiu G, Ng S‐P, et al., Direct detection of two different tumor‐derived extracellular vesicles by SAM‐AuNIs LSPR biosensor. Biosens Bioelectron 2017; 94: 400–407. [DOI] [PubMed] [Google Scholar]
83. Li T‐D, Zhang R, Chen H, Huang ZP, Ye X, Wang H, Deng AM, Kong JL, An ultrasensitive polydopamine bi‐functionalized SERS immunoassay for exosome‐based diagnosis and classification of pancreatic cancer. Chem Sci 2018; 9(24): 5372–5382. [DOI] [PMC free article] [PubMed] [Google Scholar]
84. Li A, Zhang T, Zheng M, Liu Y, Chen Z, Exosomal proteins as potential markers of tumor diagnosis. J Hematol Oncol 2017; 10(1): 175. [DOI] [PMC free article] [PubMed] [Google Scholar]
85. Wu C‐X, Liu Z‐F, Proteomic profiling of sweat exosome suggests its involvement in skin immunity. J Invest Dermatol 2018; 138(1): 89–97. [DOI] [PubMed] [Google Scholar]
86. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H, Man Q, Zhong W, Antelo LF, Wu B, Xiong X, Liu X, Guan L, Li T, Liu S, Yang R, Lu Y, Dong L, McGettigan S, Somasundaram R, Radhakrishnan R, Mills G, Lu Y, Kim J, Chen YH, Dong H, Zhao Y, Karakousis GC, Mitchell TC, Schuchter LM, Herlyn M, Wherry EJ, Xu X, Guo W, Exosomal PD‐L1 contributes to immunosuppression and is associated with anti‐PD‐1 response. Nature 2018; 560(7718): 382–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
87. Vanni I, Alama A, Grossi F, Dal Bello MG, Coco S, Exosomes: a new horizon in lung cancer. Drug Discov Today 2017; 22(6): 927–936. [DOI] [PubMed] [Google Scholar]
88. Jiang L, Shen Y, Guo D, Yang D, Liu J, Fei X, Yang Y, Zhang B, Lin Z, Yang F, Wang X, Wang K, Wang J, Cai Z, EpCAM‐dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance. Nat Commun 2016; 7: 13045–13045. [DOI] [PMC free article] [PubMed] [Google Scholar]
89. Etayash H, McGee AR, Kaur K, et al., Nanomechanical sandwich assay for multiple cancer biomarkers in breast cancer cell‐derived exosomes. Nanoscale 2016; 8(33): 15137–15141. [DOI] [PubMed] [Google Scholar]
90. Huang M, Yang J, Wang T, Song J, Xia J, Wu L, Wang W, Wu Q, Zhu Z, Song Y, Yang C, Homogeneous, low‐volume, efficient, and sensitive quantitation of circulating Exosomal PD‐L1 for cancer diagnosis and immunotherapy response prediction. Angew Chem Int Ed Engl 2020; 59(12): 4800–4805. [DOI] [PubMed] [Google Scholar]
91. Zhu C, Li L, Wang Z, Irfan M, Qu F, Recent advances of aptasensors for exosomes detection. Biosens Bioelectron 2020; 160: 112213. [DOI] [PubMed] [Google Scholar]
92. Betzer O, Perets N, Angel A, Motiei M, Sadan T, Yadid G, Offen D, Popovtzer R, In vivo neuroimaging of exosomes using gold nanoparticles. ACS Nano 2017; 11(11): 10883–10893. [DOI] [PubMed] [Google Scholar]
93. Madhankumar AB, Mrowczynski OD, Patel SR, Weston CL, Zacharia BE, Glantz MJ, Siedlecki CA, Xu LC, Connor JR, Interleukin‐13 conjugated quantum dots for identification of glioma initiating cells and their extracellular vesicles. Acta Biomater 2017; 58: 205–213. [DOI] [PubMed] [Google Scholar]
94. Zhu N, Li G, Zhou J, Zhang Y, Kang K, Ying B, Yi Q, Wu Y, A light‐up fluorescence resonance energy transfer magnetic aptamer‐sensor for ultra‐sensitive lung cancer exosome detection. J Mater Chem B 2021; 9(10): 2483–2493. [DOI] [PubMed] [Google Scholar]
95. Zhang M, Vojtech L, Ye Z, Hladik F, Nance E, Quantum dot Labeling and visualization of extracellular vesicles. ACS Appl Nano Mater 2020; 3(7): 7211–7222. [DOI] [PMC free article] [PubMed] [Google Scholar]
96. Rodrigues M, Richards N, Ning B, Lyon CJ, Hu TY, Rapid lipid‐based approach for normalization of quantum‐dot‐detected biomarker expression on extracellular vesicles in complex biological samples. Nano Lett 2019; 19(11): 7623–7631. [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Zong S, Zong J, Chen C, Jiang X, Zhang Y, Wang Z, Cui Y, Single molecule localization imaging of exosomes using blinking silicon quantum dots. Nanotechnology 2018; 29(6): 065705. [DOI] [PubMed] [Google Scholar]
98. Wu M, Chen Z, Xie Q, Xiao B, Zhou G, Chen G, Bian Z, One‐step quantification of salivary exosomes based on combined aptamer recognition and quantum dot signal amplification. Biosens Bioelectron 2021; 171: 112733. [DOI] [PubMed] [Google Scholar]
99. Liu X, Wu Y, Wu X, Zhao JX, A graphene oxide‐based fluorescence assay for the sensitive detection of DNA exonuclease enzymatic activity. Analyst 2019; 144(21): 6231–6239. [DOI] [PubMed] [Google Scholar]
100. Hwang DW, Choi Y, Kim D, Park HY, Kim KW, Kim MY, Park CK, Lee DS, Graphene oxide‐quenching‐based fluorescence in situ hybridization (G‐FISH) to detect RNA in tissue: simple and fast tissue RNA diagnostics. Nanomed Nanotech Biol Med 2019; 16: 162–172. [DOI] [PubMed] [Google Scholar]
101. Wang H, Chen H, Huang Z, Li T, Deng A, Kong J, DNase I enzyme‐aided fluorescence signal amplification based on graphene oxide‐DNA aptamer interactions for colorectal cancer exosome detection. Talanta 2018; 184: 219–226. [DOI] [PubMed] [Google Scholar]
102. Zhang Q, Wang F, Zhang H, Zhang Y, Liu M, Liu Y, Universal Ti(3)C(2) MXenes based self‐standard Ratiometric fluorescence resonance energy transfer platform for highly sensitive detection of exosomes. Anal Chem 2018; 90(21): 12737–12744. [DOI] [PubMed] [Google Scholar]
103. Wang S, Zhang L, Wan S, Cansiz S, Cui C, Liu Y, Cai R, Hong C, Teng IT, Shi M, Wu Y, Dong Y, Tan W, Aptasensor with expanded nucleotide using DNA nanotetrahedra for electrochemical detection of cancerous exosomes. ACS Nano 2017; 11(4): 3943–3949. [DOI] [PMC free article] [PubMed] [Google Scholar]
104. Xia Y, Liu M, Wang L, Yan A, He W, Chen M, Lan J, Xu J, Guan L, Chen J, A visible and colorimetric aptasensor based on DNA‐capped single‐walled carbon nanotubes for detection of exosomes. Biosens Bioelectron 2017; 92: 8–15. [DOI] [PubMed] [Google Scholar]
105. Wang YM, Liu JW, Adkins GB, Shen W, Trinh MP, Duan LY, Jiang JH, Zhong W, Enhancement of the intrinsic peroxidase‐like activity of graphitic carbon nitride nanosheets by ssDNAs and its application for detection of exosomes. Anal Chem 2017; 89(22): 12327–12333. [DOI] [PMC free article] [PubMed] [Google Scholar]
106. Boriachek K, Masud MK, Palma C, Phan HP, Yamauchi Y, Hossain MSA, Nguyen NT, Salomon C, Shiddiky MJA, Avoiding pre‐isolation step in exosome analysis: direct isolation and sensitive detection of exosomes using gold‐loaded nanoporous ferric oxide nanozymes. Anal Chem 2019; 91(6): 3827–3834. [DOI] [PubMed] [Google Scholar]
107. Jiang Y, Shi M, Liu Y, Wan S, Cui C, Zhang L, Tan W, Aptamer/AuNP biosensor for colorimetric profiling of exosomal proteins. Angew Chem Int Ed Engl 2017; 56(39): 11916–11920. [DOI] [PMC free article] [PubMed] [Google Scholar]
108. Liang K, Liu F, Fan J, Sun D, Liu C, Lyon CJ, Bernard DW, Li Y, Yokoi K, Katz MH, Koay EJ, Zhao Z, Hu Y, Nanoplasmonic quantification of tumour‐derived extracellular vesicles in plasma microsamples for diagnosis and treatment monitoring. Nat Biomed Eng. 2017; 1(4): 0021. [DOI] [PMC free article] [PubMed] [Google Scholar]
109. Fan Y, Duan X, Zhao M, Wei X, Wu J, Chen W, Liu P, Cheng W, Cheng Q, Ding S, High‐sensitive and multiplex biosensing assay of NSCLC‐derived exosomes via different recognition sites based on SPRi array. Biosens Bioelectron 2020; 154: 112066. [DOI] [PubMed] [Google Scholar]
110. Liao G, Liu X, Yang X, Wang Q, Geng X, Zou L, Liu Y, Li S, Zheng Y, Wang K, Surface plasmon resonance assay for exosomes based on aptamer recognition and polydopamine‐functionalized gold nanoparticles for signal amplification. Microchim Acta 2020; 187(4): 251. [DOI] [PubMed] [Google Scholar]
111. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M, A comprehensive overview of exosomes as drug delivery vehicles—endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 2014; 1846(1): 75–87. [DOI] [PubMed] [Google Scholar]
112. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R, Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 2021; 20(2): 101–124. [DOI] [PMC free article] [PubMed] [Google Scholar]
113. Pan S, Pei L, Zhang A, Zhang Y, Zhang C, Huang M, Huang Z, Liu B, Wang L, Ma L, Zhang Q, Cui D, Passion fruit‐like exosome‐PMA/Au‐BSA@Ce6 nanovehicles for real‐time fluorescence imaging and enhanced targeted photodynamic therapy with deep penetration and superior retention behavior in tumor. Biomaterials 2020; 230: 119606. [DOI] [PubMed] [Google Scholar]
114. Liu Q, Fan T, Zheng Y, Yang SL, Yu Z, Duo Y, Zhang Y, Adah D, Shi L, Sun Z, Wang D, Xie J, Wu H, Wu Z, Ge C, Qiao L, Wei C, Huang L, Yan Q, Yang Q, Bao S, Liu LP, Zhang H, Immunogenic exosome‐encapsulated black phosphorus nanoparticles as an effective anticancer photo‐nanovaccine. Nanoscale 2020; 12(38): 19939–19952. [DOI] [PubMed] [Google Scholar]
115. Cao Y, Wu T, Zhang K, Meng X, Dai W, Wang D, Dong H, Zhang X, Engineered exosome‐mediated near‐infrared‐II region V2C quantum dot delivery for nucleus‐target low‐temperature Photothermal therapy. ACS Nano 2019; 13(2): 1499–1510. [DOI] [PubMed] [Google Scholar]
116. Illes B, Hirschle P, Barnert S, Cauda V, Wuttke S, Engelke H, Exosome‐coated metal–organic framework nanoparticles: An efficient drug delivery platform. Chem Mater 2017; 29(19): 8042–8046. [Google Scholar]
117. 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. [DOI] [PubMed] [Google Scholar]
118. Sancho‐Albero M, Rubio‐Ruiz B, Pérez‐López AM, Sebastián V, Martín‐Duque P, Arruebo M, Santamaría J, Unciti‐Broceta A, Cancer‐derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis. Nat Catal 2019; 2(10): 864–872. [DOI] [PMC free article] [PubMed] [Google Scholar]
119. Sebastian V, Sancho‐Albero M, Arruebo M, Pérez‐López AM, Rubio‐Ruiz B, Martin‐Duque P, Unciti‐Broceta A, Santamaría J, Nondestructive production of exosomes loaded with ultrathin palladium nanosheets for targeted bio‐orthogonal catalysis. Nat Protoc 2021; 16(1): 131–163. [DOI] [PubMed] [Google Scholar]
120. Vines JB, Yoon JH, Ryu NE, Lim DJ, Park H, Gold nanoparticles for Photothermal cancer therapy. Front Chem 2019; 7: 167. [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Sancho‐Albero M, Navascués N, Mendoza G, Sebastián V, Arruebo M, Martín‐Duque P, Santamaría J, Exosome origin determines cell targeting and the transfer of therapeutic nanoparticles towards target cells. J Nanobiotechnol. 2019; 17(1): 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
122. Théry C, Ostrowski M, Segura E, Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9(8): 581–593. [DOI] [PubMed] [Google Scholar]
123. Alvarez‐Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA, Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29(4): 341–345. [DOI] [PubMed] [Google Scholar]
124. Cao Y, Wu T, Zhang K, Meng X, Dai W, Wang D, Dong H, Zhang X, Engineered exosome‐mediated near‐infrared‐II region V(2)C quantum dot delivery for nucleus‐target low‐temperature Photothermal therapy. ACS Nano 2019; 13(2): 1499–1510. [DOI] [PubMed] [Google Scholar]
125. Zhu M, Li Y, Shi J, Feng W, Nie G, Zhao Y, Exosomes as extrapulmonary signaling conveyors for nanoparticle‐induced systemic immune activation. Small 2012; 8(3): 404–412. [DOI] [PubMed] [Google Scholar]
126. Liu S, Chen X, Bao L, Liu T, Yuan P, Yang X, Qiu X, Gooding JJ, Bai Y, Xiao J, Pu F, Jin Y, Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody‐conjugated magnetic nanoparticles. Nat Biomed Eng 2020; 4(11): 1063–1075. [DOI] [PubMed] [Google Scholar]
127. Chistiakov DA, Orekhov AN, Bobryshev YV, Cardiac extracellular vesicles in Normal and infarcted heart. Int J Mol Sci 2016; 17(1): 63. [DOI] [PMC free article] [PubMed] [Google Scholar]
128. Kalani A, Tyagi A, Tyagi N, Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol 2014; 49(1): 590–600. [DOI] [PMC free article] [PubMed] [Google Scholar]
129. Perets N, Betzer O, Shapira R, Brenstein S, Angel A, Sadan T, Ashery U, Popovtzer R, Offen D, Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Lett 2019; 19(6): 3422–3431. [DOI] [PubMed] [Google Scholar]
130. Tong M, Chamley LW, Placental extracellular vesicles and feto‐maternal communication. Cold Spring Harb Perspect Med 2015; 5(3): a023028. [DOI] [PMC free article] [PubMed] [Google Scholar]
131. Srivastava A, Amreddy N, Babu A, Panneerselvam J, Mehta M, Muralidharan R, Chen A, Zhao YD, Razaq M, Riedinger N, Kim H, Liu S, Wu S, Abdel‐Mageed AB, Munshi A, Ramesh R, Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci Rep 2016; 6(1): 38541. [DOI] [PMC free article] [PubMed] [Google Scholar]
132. Rosi NL, Giljohann DA, Thaxton CS, Lytton‐Jean AKR, Han MS, Mirkin CA, Oligonucleotide‐modified gold nanoparticles for intracellular gene regulation. Science 2006; 312(5776): 1027–1030. [DOI] [PubMed] [Google Scholar]
133. Alhasan AH, Patel PC, Choi CH, et al., Exosome encased spherical nucleic acid gold nanoparticle conjugates as potent microRNA regulation agents. Small 2014; 10(1): 186–192. [DOI] [PMC free article] [PubMed] [Google Scholar]
134. Zhan Q, Yi K, Qi H, Li S, Li X, Wang Q, Wang Y, Liu C, Qiu M, Yuan X, Zhao J, Hou X, Kang C, Engineering blood exosomes for tumor‐targeting efficient gene/chemo combination therapy. Theranostics 2020; 10(17): 7889–7905. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

There are no supplementary data available for this article.

PERMALINK

Tango of dual nanoparticles: Interplays between exosomes and nanomedicine

Yabin Wang

Wenzhen Wang

Fangong Kong

Qiu Zhang

Jiaqi Xiao

Yi Zhang

Bing Yan

Abstract

1. NPS FOR EXOSOME BIOGENESIS REGULATION

2. NPS FOR EXOSOME PURIFICATION

TABLE 1.

FIGURE 1.

3. NPS FOR QUANTITATIVE EXOSOMES DETECTION

TABLE 2.

3.1. Fluorescence‐based detection

FIGURE 2.

3.2. Electrochemistry‐based detection

3.3. Colorimetry‐based detection

3.4. Resonance‐based detection

FIGURE 3.

4. EXOSOMES FOR NPS‐BASED DISEASE THERAPY

TABLE 3.

4.1. In tumor therapy

FIGURE 4.

4.2. In therapy for other diseases

FIGURE 5.

5. CONCLUSIONS AND PERSPECTIVES

CONFLICT OF INTEREST

AUTHOR CONTRIBUTIONS

PEER REVIEW

ACKNOWLEDGMENT

Contributor Information

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases