Extracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines

doi:10.1016/j.semcdb.2016.12.001

Seminars in Cell & Developmental Biology

Volume 67, July 2017, Pages 74-82

https://doi.org/10.1016/j.semcdb.2016.12.001 Get rights and content

Abstract

Extracellular vesicles are nano-sized spherical bilayered proteolipids encasing various components. Cells of all domains of life actively release these vesicles to the surroundings including various biological fluids. These extracellular vesicles are known to play pivotal roles in numerous pathophysiological functions. Extracellular vesicles have distinct characteristics, like high biocompatibility, safety, and nano-sized diameters that allow efficient drug loading capacity and long blood circulation half-life. These characteristics of extracellular vesicles have engrossed many scientists to harness them as new tools for novel delivery systems. This review will highlight the current state of the arts and problems of such extracellular vesicle-based theranostics, drug delivery and vaccines, and introduce “extracellular vesicle mimetics” as the novel alternative of extracellular vesicles. We hope to provide insights into the potential of extracellular vesicle mimetics as superior substitute to the natural extracellular vesicles that can be applied to theranostics, drug delivery, and vaccines against various diseases.

Introduction

Extracellular vesicles are lipid-bilayered spherical entities of nano-meters in size encompassing bioactive cellular components like proteins, lipids, metabolites, and nucleic acids [1], [2], [3], [4]. They are constitutively and actively shed by most of the cells from all domains of life including eukaryotes, bacteria, and archaea [1], [2], [3], [4]. Recent advancement on the studies verifying the existence of extracellular vesicles in various biological fluids, like the blood plasma, serum, urine, ascites, saliva, breast milk, and in amniotic fluids, together with the recognizing of their roles as modulators of plethora of pathophysiological functions have engrossed many scientists to harness these vesicles as powerful source of diagnostic and therapeutic agents against various diseases and drug/vaccine delivery system [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21].

This review will address the current state of the arts and limitations of extracellular vesicle-based theranostics, drug delivery and vaccines and introduce “extracellular vesicle mimetics” as the superior alternative of natural extracellular vesicles as theranostics, drug delivery and vaccines. In detail, we will cover various studies on the applications of extracellular vesicles from both mammalian and bacterial origin and their limitations. We will also introduce the techniques and studies used by our group and others in making “extracellular vesicle mimetics” to overcome the problems faced when using natural form of extracellular vesicles.

Section snippets

Mammalian extracellular vesicles

Mammalian cells, including endothelial cells, immune cells, epithelial cells, and mesenchymal stem cells as well as cancer cells release extracellular vesicles into the surroundings [22]. In addition, extracellular vesicles are found in virtually all biological fluids, such as the urine, blood, breast milk, and saliva [23]. Known to function as communicasomes mediating cell-to-cell communication, these extracellular vesicles harbor various bioactive components important for modulating

Bacterial extracellular vesicles

First observed through the electron microscopy studies in the 1960s, Gram-negative bacterial extracellular vesicles, more commonly known as outer membrane vesicles, are vesicles secreted from Gram-negative bacteria with an average diameter of 20–200 nm [1], [79], [80], [81], [82]. Although the secretion of extracellular vesicles from Gram-positive bacteria with a thick cell wall had been overlooked for many years, it is now understood that Gram-positive bacteria can also release extracellular

Extracellular vesicle-mimetic nanovesicles

A viable alternative for extracellular vesicle-based therapeutics and drug delivery systems is synthetically tailored extracellular vesicle-mimetic nanovesicles. Production of such extracellular vesicle mimetics may allow scalable production for use in clinical settings. Moreover, the use of extracellular vesicle mimetics can make formation of sterile, well characterized form of therapeutics and delivery systems. However, especially when used as therapeutics or vaccines, such steamlined

Concluding remarks

The design and development of safe and effective vaccines, therapeutics, and drug delivery systems to the target site are fields that have increasingly gained attention over the last decades. Growing number of studies are now shifting their focus from synthetic compounds to biological compounds that can achieve better efficacy and safety. Extracellular vesicles have played some roles in making such shift. Extracellular vesicles are found to be fundamentally involved in many pathophysiological

Acknowledgements

This study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A2A1A10055961).

References (118)

N. Soler et al.
Virus-like vesicles and extracellular DNA produced by hyperthermophilic archaea of the order Thermococcales
Res. Microbiol.
(2008)
S. Keller et al.
CD24 is a marker of exosomes secreted into urine and amniotic fluid
Kidney Int.
(2007)
R.C. Wiggins et al.
Procoagulant activity in normal human urine associated with subcellular particles
Kidney Int.
(1986)
J.N. George et al.
Isolation of human platelet membrane microparticles from plasma and serum
Blood
(1982)
D. Sun et al.
A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes
Mol. Ther.
(2010)
R.C. Lai et al.
Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury
Stem Cell Res.
(2010)
D.K. Kim et al.
EVpedia: a community web resource for prokaryotic and eukaryotic extracellular vesicles research
Semin. Cell Dev. Biol.
(2015)
P. Vader et al.
Extracellular vesicles: emerging targets for cancer therapy
Trends Mol. Med.
(2014)
S.M. van Dommelen et al.
Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery
J. Control. Release
(2012)
A. Aharon et al.
Microparticles, thrombosis and cancer
Best Pract. Res. Clin. Haematol.
(2009)

M. Simons et al.

Exosomes–vesicular carriers for intercellular communication

Curr. Opin. Cell Biol.

(2009)

D. Ha et al.

Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges

Acta Pharm. Sin. B

(2016)

G. Lachenal et al.

Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity

Mol. Cell. Neurosci.

(2011)

R. Ghidoni et al.

Exosomes: the Trojan horses of neurodegeneration

Med. Hypotheses

(2008)

A.E. Morelli et al.

Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells

Blood

(2004)

J.L. Hood et al.

Consortium for translational research in advanced I, nanomedicine. Paracrine induction of endothelium by tumor exosomes

Lab. Invest.

(2009)

H. Tadokoro et al.

Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells

J. Biol. Chem.

(2013)

A.V. Vlassov et al.

Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials

Biochim. Biophys. Acta

(2012)

A.Z. Wilczewska et al.

Nanoparticles as drug delivery systems

Pharmacol. Rep.

(2012)

U. Agrawal et al.

Is nanotechnology a boon for oral drug delivery

Drug Discov. Today

(2014)

S. Ohno et al.

Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells

Mol. Ther.

(2013)

X. Zhuang et al.

Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain

Mol. Ther.

(2011)

J.H. Kim et al.

Gram-negative and Gram-positive bacterial extracellular vesicles

Semin. Cell Dev. Biol.

(2015)

K.E. Bonnington et al.

Protein selection and export via outer membrane vesicles

Biochim. Biophys. Acta

(2014)

E. Namork et al.

Fatal meningococcal septicaemia with blebbing meningococcus

Lancet

(2002)

R. Dalseg et al.

Outer membrane vesicles from group B meningococci are strongly immunogenic when given intranasally to mice

Vaccine

(1999)

M.J. McConnell et al.

Outer membrane vesicles as an acellular vaccine against Acinetobacter baumannii

Vaccine

(2011)

J. Keenan et al.

A role for the bacterial outer membrane in the pathogenesis of Helicobacter pylori infection

FEMS Microbiol. Lett.

(2000)

K.W. Knox et al.

Relation between excreted lipopolysaccharide complexes and surface structures of a lysine-limited culture of Escherichia coli

J. Bacteriol.

(1966)

E.Y. Lee et al.

Gram-positive bacteria produce membrane vesicles: proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles

Proteomics

(2009)

P. Wolf

The nature and significance of platelet products in human plasma

Br. J. Haematol.

(1967)

E.Y. Lee et al.

Proteomics in Gram-negative bacterial outer membrane vesicles

Mass Spectrom. Rev.

(2008)

C. Thery et al.

Membrane vesicles as conveyors of immune responses

Nat. Rev. Immunol.

(2009)

D.S. Choi et al.

Proteomic analysis of microvesicles derived from human colorectal cancer ascites

Proteomics

(2011)

Y. Ogawa et al.

Exosome-like vesicles with dipeptidyl peptidase IV in human saliva

Biol. Pharm. Bull.

(2008)

C. Admyre et al.

Exosomes with immune modulatory features are present in human breast milk

J. Immunol.

(2007)

J. Ratajczak et al.

Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication

Leukemia

(2006)

H.F. Dvorak et al.

Tumor shedding and coagulation

Science

(1981)

G. Ronquist et al.

An Mg²⁺ and Ca²⁺-stimulated adenosine triphosphatase in human prostatic fluid: part I

Andrologia

(1978)

S.C. Jang et al.

In vivo kinetic biodistribution of nano-sized outer membrane vesicles derived from bacteria

Small

(2015)

S.C. Jang et al.

Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors

ACS Nano

(2013)

E.Y. Lee et al.

Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis

PLoS One

(2012)

L. Alvarez-Erviti et al.

Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes

Nat. Biotechnol.

(2011)

D.S. Choi et al.

Proteomics, transcriptomics and lipidomics of exosomes and ectosomes

Proteomics

(2013)

D.S. Choi et al.

Circulating extracellular vesicles in cancer diagnosis and monitoring: an appraisal of clinical potential

Mol. Diagn. Ther.

(2013)

S. El Andaloussi et al.

Extracellular vesicles: biology and emerging therapeutic opportunities

Nat. Rev. Drug Discov.

(2013)

D.K. Kim et al.

EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles

J. Extracell. Vesicles

(2013)

R. van der Meel et al.

Toward routine detection of extracellular vesicles in clinical samples

Int. J. Lab. Hematol.

(2014)

S.A. Kooijmans et al.

Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems

Int. J. Nanomed.

(2012)

Y. Lee et al.

Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy

Hum. Mol. Genet.

(2012)

Cited by (64)

Biomimetic nanovesicles-based therapeutic strategy for alleviating intervertebral disc degeneration via integration with mechanically responsive miR-1249
2024, Nano Today
Intervertebral disc degeneration (IDD) is an important cause of disability worldwide, where abnormal compressive loading plays a crucial role. Several microRNAs (miRNAs) have been reported to be involved in IDD. However, mechanically responsive miRNAs in IDD have not been fully investigated. Furthermore, the deficiency of an effective miRNA delivery system is a key prerequisite for achieving intradiscal therapy. In the present study, mechanically responsive miR-1249 is identified via miRNA-sequencing to be down-regulated in compression-induced IDD of rats. It is further revealed that miR-1249 exerts a protective effect on the metabolism of the extracellular matrix of the nucleus pulposus (NP) by targeting Nrarp. Based on the mechanism study, extracellular vesicle-mimetic nanovesicles are developed by extruding NP cells as a miRNA therapeutic system to integrate with miR-1249 mimics (NV-mimics). In vivo, the local injection of NV-mimics could effectively alleviate the progression of abnormal compressive stress-induced IDD, including the retention of the water content and height of the disks, the conservation of the NP tissues, and the improvement of imbalance metabolism of extracellular matrix, which is evidenced by imaging examination and histological analyses, respectively. The present study provides a promising therapeutic strategy for delaying the progression of IDD.
The functions and applications of extracellular vesicles derived from Mycobacterium tuberculosis
2023, Biomedicine and Pharmacotherapy
Extracellular vesicles (EVs) originating from bacteria function critical roles in bacterial biologic physiology and host-pathogen interactions. Mycobacterium tuberculosis (M. tuberculosis) produces EVs both in vitro and in vivo, with membrane-bound nanoparticles facilitating the transmission of biological molecules including lipids, proteins, nucleic acids and glycolipids, while interacting remotely with the host. Although studies of EVs in mycobacterial infections is still in its infancy, it has already revealed an entirely new aspect of M. tuberculosis-host interactions that may have implications for tuberculosis (TB) pathogenesis. In this review, we discuss the significant functions of M. tuberculosis EVs in elucidating the mechanisms underlying vesicle biogenesis and modulating cellular immune responses, as well as the recent advances and challenges in the development of novel preventive and therapeutic or diagnostic strategies against TB.
New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis
2023, Biomedicine and Pharmacotherapy
In 1971, Folkman proposed that tumors could be limited to very small sizes by blocking angiogenesis. Angiogenesis is the generation of new blood vessels from pre-existing vessels, considered to be one of the important processes in tumor growth and metastasis. Angiogenesis is a complex process regulated by various factors and involves many secreted factors and signaling pathways. Angiogenesis is important in the transport of oxygen and nutrients to the tumor during tumor development. Therefore, inhibition of angiogenesis has become an important strategy in the clinical management of many solid tumors. Combination therapies of angiogenesis inhibitors with radiotherapy and chemotherapy are often used in clinical practice. In this article, we will review common targets against angiogenesis, the most common and up-to-date anti-angiogenic drugs and clinical treatments in recent years, including active ingredients from chemical and herbal medicines.
Functional enhancement of exosomes derived from NK cells by IL-15 and IL-21 synergy against hepatocellular carcinoma cells: The cytotoxicity and apoptosis in vitro study
2023, Heliyon
Exosomes are released by various cells, including natural killer (NK) cells and transport signaling molecules for the intercellular communication. Hepatocellular carcinoma (HCC), also known as primary liver cancer, is often inoperable and difficult to accurate diagnosis. Notably, the prognosis and underlying mechanisms of HCC are not fully understood. Exosomes-derived NK cells (NK-exos) express unique cytotoxic proteins with a killing ability in tumors and can easily penetrate tumor tissues to improve their targeting ability. NK cell functions, inducing cellular cytotoxicity are modulated by cytokines such as interleukin (IL)-15 and IL-21. However, the mechanisms and effects of cytokines-stimulated NK-exos for the treatment of liver cancer, including HCC, are not well known. In this study, we aimed to investigate the synergistic anti-tumor effects of NK-exos stimulated with IL-15 and IL-21 (NK-exos^IL−15/21) in Hep3B cells. Our findings revealed that NK-exos^IL−15/21 expressed cytotoxic proteins (perforin and granzyme B) and contained typical exosome markers (CD9 and CD63) within the size range of 100–150 nm. Moreover, we demonstrated that NK-exos^IL−15/21 induced the enhancement of cytotoxicity and apoptotic activity in Hep3B cells by activating the specific pro-apoptotic proteins (Bax, cleaved caspase 3, cleaved PARP, perforin, and granzyme B) and inhibiting the anti-apoptotic protein (Bcl-2). In summary, our results suggest that NK-exos^IL−15/21 regulate strong anti-tumor effects of HCC cells, by increasing the cytotoxicity and apoptosis through the activation of specific cytotoxic molecules.
Advances in developing ACE2 derivatives against SARS-CoV-2
2023, The Lancet Microbe
Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune evasion capacity through key amino acid mutations, but can still bind human angiotensin-converting enzyme 2 (ACE2) through the spike protein and are, thus, sensitive to ACE2-mimicking decoys as inhibitors. In this Review, we examine advances in the development of ACE2 derivatives from the past 3 years, including the recombinant ACE2 proteins, ACE2-loaded extracellular vesicles, ACE2-mimicking antibodies, and peptide or mini-protein mimetics of ACE2. Several ACE2 derivatives are granted potent neutralisation efficacy against SARS-CoV-2 variants that rival or surpass endogenous antibodies by various auxiliary techniques such as chemical modification and practical recombinant design. The derivatives also represent enhanced production efficiency and improved bioavailability. In addition to these derivatives of ACE2, new effective therapeutics against SARS-CoV-2 variants are expected to be developed.
Synthesized nanoparticles, biomimetic nanoparticles and extracellular vesicles for treatment of autoimmune disease: Comparison and prospect
2021, Pharmacological Research
An emerging strategy is needed to treat autoimmune diseases, many of which are chronic with no definitive cure. Current treatments only alleviate symptoms and have many side effects affecting patient quality of life. Recently, nanoparticle drug delivery systems, an emerging method in medicine, has been used to target cells or organs, without damaging normal tissue. This approach has led to fewer side effects, along with a strong immunosuppressive capacity. Therefore, a nanotechnology approach may help to improve the treatment of autoimmune diseases. In this review, we separated nanoparticles into three categories: synthesized nanoparticles, biomimetic nanoparticles, and extracellular vesicles. This review firstly compares the typical mechanism of action of these three nanoparticle categories respectively in terms of active targeting, camouflage effect, and similarity to parent cells. Then their immunomodulation properties are discussed. Finally, the challenges faced by all these nanoparticles are described.

View all citing articles on Scopus

View full text

ReviewExtracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines

Abstract

Introduction

Section snippets

Mammalian extracellular vesicles

Bacterial extracellular vesicles

Extracellular vesicle-mimetic nanovesicles

Concluding remarks

Acknowledgements

Res. Microbiol.

Kidney Int.

Kidney Int.

Blood

Mol. Ther.

Stem Cell Res.

Semin. Cell Dev. Biol.

Trends Mol. Med.

J. Control. Release

Best Pract. Res. Clin. Haematol.

Curr. Opin. Cell Biol.

Acta Pharm. Sin. B

Mol. Cell. Neurosci.

Med. Hypotheses

Blood

Lab. Invest.

J. Biol. Chem.

Biochim. Biophys. Acta

Pharmacol. Rep.

Drug Discov. Today

Mol. Ther.

Mol. Ther.

Semin. Cell Dev. Biol.

Biochim. Biophys. Acta

Lancet

Vaccine

Vaccine

FEMS Microbiol. Lett.

Relation between excreted lipopolysaccharide complexes and surface structures of a lysine-limited culture of Escherichia coli

J. Bacteriol.

Gram-positive bacteria produce membrane vesicles: proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles

Proteomics

The nature and significance of platelet products in human plasma

Br. J. Haematol.

Proteomics in Gram-negative bacterial outer membrane vesicles

Mass Spectrom. Rev.

Membrane vesicles as conveyors of immune responses

Nat. Rev. Immunol.

Proteomic analysis of microvesicles derived from human colorectal cancer ascites

Proteomics

Exosome-like vesicles with dipeptidyl peptidase IV in human saliva

Biol. Pharm. Bull.

Exosomes with immune modulatory features are present in human breast milk

J. Immunol.

Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication

Leukemia

Tumor shedding and coagulation

Science

An Mg2+ and Ca2+-stimulated adenosine triphosphatase in human prostatic fluid: part I

Andrologia

In vivo kinetic biodistribution of nano-sized outer membrane vesicles derived from bacteria

Small

Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors

ACS Nano

Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis

PLoS One

Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes

Nat. Biotechnol.

Proteomics, transcriptomics and lipidomics of exosomes and ectosomes

Proteomics

Circulating extracellular vesicles in cancer diagnosis and monitoring: an appraisal of clinical potential

Mol. Diagn. Ther.

Extracellular vesicles: biology and emerging therapeutic opportunities

Nat. Rev. Drug Discov.

EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles

J. Extracell. Vesicles

Toward routine detection of extracellular vesicles in clinical samples

Int. J. Lab. Hematol.

Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems

Int. J. Nanomed.

Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy

Review
Extracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines

An Mg²⁺ and Ca²⁺-stimulated adenosine triphosphatase in human prostatic fluid: part I