Advances in therapeutic applications of extracellular vesicles

Extracellular vesicles (EVs) are nanometer-sized, lipid membrane–enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.

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Extracellular Vesicles as Biological Shuttles for Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms20081848 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1848 ◽

Cited By ~ 20

Author(s):

Stefania Raimondo ◽

Gianluca Giavaresi ◽

Aurelio Lorico ◽

Riccardo Alessandro

Keyword(s):

Extracellular Vesicles ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

Target Cells ◽

Special Focus ◽

Pathological Conditions ◽

Critical Issues ◽

Membrane Bound ◽

And Function ◽

Potential Use

The development of effective nanosystems for drug delivery represents a key challenge for the improvement of most current anticancer therapies. Recent progress in the understanding of structure and function of extracellular vesicles (EVs)—specialized membrane-bound nanocarriers for intercellular communication—suggests that they might also serve as optimal delivery systems of therapeutics. In addition to carrying proteins, lipids, DNA and different forms of RNAs, EVs can be engineered to deliver specific bioactive molecules to target cells. Exploitation of their molecular composition and physical properties, together with improvement in bio-techniques to modify their content are critical issues to target them to specific cells/tissues/organs. Here, we will discuss the current developments in the field of animal and plant-derived EVs toward their potential use for delivery of therapeutic agents in different pathological conditions, with a special focus on cancer.

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Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

Pharmaceutics ◽

10.3390/pharmaceutics13040492 ◽

2021 ◽

Vol 13 (4) ◽

pp. 492

Author(s):

Charlotte A. René ◽

Robin J. Parks

Keyword(s):

Central Nervous System ◽

Endothelial Cells ◽

Nervous System ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Therapeutic Agents ◽

Target Cells ◽

Significant Barrier ◽

The Central Nervous System ◽

Delivery Vehicles

The central nervous system (CNS) is surrounded by the blood–brain barrier (BBB), a semipermeable border of endothelial cells that prevents pathogens, solutes and most molecules from non-selectively crossing into the CNS. Thus, the BBB acts to protect the CNS from potentially deleterious insults. Unfortunately, the BBB also frequently presents a significant barrier to therapies, impeding passage of drugs and biologicals to target cells within the CNS. This review provides an overview of different approaches to deliver therapeutics across the BBB, with an emphasis in extracellular vesicles as delivery vehicles to the CNS.

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Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

International Journal of Molecular Sciences ◽

10.3390/ijms21010266 ◽

2019 ◽

Vol 21 (1) ◽

pp. 266 ◽

Cited By ~ 9

Author(s):

Gabriella Schiera ◽

Carlo Maria Di Liegro ◽

Italia Di Liegro

Keyword(s):

Learning And Memory ◽

Extracellular Vesicles ◽

Glial Cells ◽

Information Exchange ◽

System Development ◽

Cell Communication ◽

Nervous System Development ◽

The Body ◽

Pathological Conditions ◽

And Function

Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

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Plasmonic Nanofactors as Switchable Devices to Promote or Inhibit Neuronal Activity and Function

Nanomaterials ◽

10.3390/nano9071029 ◽

2019 ◽

Vol 9 (7) ◽

pp. 1029 ◽

Cited By ~ 1

Author(s):

Karrer M. Alghazali ◽

Rabab N. Hamzah ◽

Zeid A. Nima ◽

Richard Steiner ◽

Madhu Dhar ◽

...

Keyword(s):

Stem Cell ◽

Neuronal Activity ◽

Tissue Regeneration ◽

Cellular Proliferation ◽

Neuronal Cells ◽

Stem Cell Differentiation ◽

Extracellular Matrices ◽

Specific Cancer ◽

Cancer Cell Targeting ◽

And Function

Gold nanosystems have been investigated extensively for a variety of applications, from specific cancer cell targeting to tissue regeneration. Specifically, a recent and exciting focus has been the gold nanosystems’ interface with neuronal biology. Researchers are investigating the ability to use these systems neuronal applications ranging from the enhancement of stem cell differentiation and therapy to stimulation or inhibition of neuronal activity. Most of these new areas of research are based on the integration of the plasmonic properties of such nanosystems into complex synthetic extracellular matrices (ECM) that can interact and affect positively the activity of neuronal cells. Therefore, the ability to integrate the plasmonic properties of these nanoparticles into multidimensional and morphological structures to support cellular proliferation and activity is potentially of great interest, particularly to address medical conditions that are currently not fully treatable. This review discusses some of the promising developments and unique capabilities offered by the integration of plasmonic nanosystems into morphologically complex ECM devices, designed to control and study the activity of neuronal cells.

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Engineered Extracellular Vesicles: Tailored-Made Nanomaterials for Medical Applications

Nanomaterials ◽

10.3390/nano10091838 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1838

Author(s):

Kenny Man ◽

Mathieu Y. Brunet ◽

Marie-Christine Jones ◽

Sophie C. Cox

Keyword(s):

Extracellular Vesicles ◽

Tissue Regeneration ◽

State Of The Art ◽

Medical Applications ◽

Clinical Use ◽

Current State ◽

Pathological Conditions ◽

Potential Efficacy ◽

Biomimetic Nanoparticles ◽

Natural Cell

Extracellular vesicles (EVs) are emerging as promising nanoscale therapeutics due to their intrinsic role as mediators of intercellular communication, regulating tissue development and homeostasis. The low immunogenicity and natural cell-targeting capabilities of EVs has led to extensive research investigating their potential as novel acellular tools for tissue regeneration or for the diagnosis of pathological conditions. However, the clinical use of EVs has been hindered by issues with yield and heterogeneity. From the modification of parental cells and naturally-derived vesicles to the development of artificial biomimetic nanoparticles or the functionalisation of biomaterials, a multitude of techniques have been employed to augment EVs therapeutic efficacy. This review will explore various engineering strategies that could promote EVs scalability and therapeutic effectiveness beyond their native utility. Herein, we highlight the current state-of-the-art EV-engineering techniques with discussion of opportunities and obstacles for each. This is synthesised into a guide for selecting a suitable strategy to maximise the potential efficacy of EVs as nanoscale therapeutics.

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Human Heart Explant-Derived Extracellular Vesicles: Characterization and Effects on the In Vitro Recellularization of Decellularized Heart Valves

International Journal of Molecular Sciences ◽

10.3390/ijms20061279 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1279 ◽

Cited By ~ 4

Author(s):

Amanda Leitolis ◽

Paula Suss ◽

João Roderjan ◽

Addeli Angulski ◽

Francisco da Costa ◽

...

Keyword(s):

Wound Healing ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Tissue Regeneration ◽

Human Heart ◽

Heart Valves ◽

Enrichment Analysis ◽

Cell Types

Extracellular vesicles (EVs) are particles released from different cell types and represent key components of paracrine secretion. Accumulating evidence supports the beneficial effects of EVs for tissue regeneration. In this study, discarded human heart tissues were used to isolate human heart-derived extracellular vesicles (hH-EVs). We used nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) to physically characterize hH-EVs and mass spectrometry (MS) to profile the protein content in these particles. The MS analysis identified a total of 1248 proteins. Gene ontology (GO) enrichment analysis in hH-EVs revealed the proteins involved in processes, such as the regulation of cell death and response to wounding. The potential of hH-EVs to induce proliferation, adhesion, angiogenesis and wound healing was investigated in vitro. Our findings demonstrate that hH-EVs have the potential to induce proliferation and angiogenesis in endothelial cells, improve wound healing and reduce mesenchymal stem-cell adhesion. Last, we showed that hH-EVs were able to significantly promote mesenchymal stem-cell recellularization of decellularized porcine heart valve leaflets. Altogether our data confirmed that hH-EVs modulate cellular processes, shedding light on the potential of these particles for tissue regeneration and for scaffold recellularization.

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Exosomes and extracellular vesicles: the path forward

Essays in Biochemistry ◽

10.1042/ebc20170088 ◽

2018 ◽

Vol 62 (2) ◽

pp. 119-124 ◽

Cited By ~ 38

Author(s):

Philip D. Stahl ◽

Graça Raposo

Keyword(s):

Extracellular Vesicles ◽

Cell Biology ◽

Biological Fluids ◽

Therapeutic Agents ◽

Tissue Homeostasis ◽

The Past ◽

And Function ◽

Intercellular Communications ◽

Biomedical Community

Over the course of the past several decades, the concept that extracellular vesicles, exosomes and microvesicles, operate as cellular “housekeepers” and as agents for communication between and among cells and tissues, has emerged into one of the most promising yet vexing problems facing the biomedical community. Already, extracellular vesicles from biological fluids are being used for diagnostic purposes and hopes abound for their use as therapeutic agents. However, the most basic mechanistic questions surrounding their biogenesis and function in cellular and tissue homeostasis remain largely unexplored. In this issue of Essays in Biochemistry, the rise of a new intercellular communications pathway is considered from many perspectives—cell biology, physiology, and pathophysiology.

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Non-coding RNAs in Mesenchymal Stem Cell-Derived Extracellular Vesicles: Deciphering Regulatory Roles in Stem Cell Potency, Inflammatory Resolve, and Tissue Regeneration

Frontiers in Genetics ◽

10.3389/fgene.2017.00161 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 53

Author(s):

Farah Fatima ◽

Karin Ekstrom ◽

Irina Nazarenko ◽

Marco Maugeri ◽

Hadi Valadi ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Tissue Regeneration ◽

Non Coding Rnas

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Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02460-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lu Yu ◽

Siying Liu ◽

Chen Wang ◽

Chuanyu Zhang ◽

Yajie Wen ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Es Cells ◽

Ischemia Reperfusion ◽

Embryonic Stem ◽

Kidney Injury ◽

Structure And Function ◽

And Function

Abstract Background Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear. Methods In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro. Results We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells. Conclusions ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.

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