scholarly journals Bovine Milk-Derived Exosomes as a Drug Delivery Vehicle for miRNA-Based Therapy

2021 ◽  
Vol 22 (3) ◽  
pp. 1105
Author(s):  
Lorena del Pozo-Acebo ◽  
M-C López de las Hazas ◽  
Joao Tomé-Carneiro ◽  
Paula Gil-Cabrerizo ◽  
Rodrigo San-Cristobal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Delivery ◽  
Therapeutic Potential ◽  
Bovine Milk ◽  
Cost Effective ◽  
Extracellular Vesicle ◽  
Size Exclusion ◽  
Target Cells ◽  
Extracellular Rna ◽  
Delivery Vehicles

MicroRNAs (miRNAs) are small non-coding RNAs with a known role as mediators of gene expression in crucial biological processes, which converts them into high potential contenders in the ongoing search for effective therapeutic strategies. However, extracellular RNAs are unstable and rapidly degraded, reducing the possibility of successfully exerting a biological function in distant target cells. Strategies aimed at enhancing the therapeutic potential of miRNAs include the development of efficient, tissue-specific and nonimmunogenic delivery methods. Since miRNAs were discovered to be naturally transported within exosomes, a type of extracellular vesicle that confers protection against RNase degradation and increases miRNA stability have been proposed as ideal delivery vehicles for miRNA-based therapy. Although research in this field has grown rapidly in the last few years, a standard, reproducible and cost-effective protocol for exosome isolation and extracellular RNA delivery is lacking. We aimed to evaluate the use of milk-derived extracellular vesicles as vehicles for extracellular RNA drug delivery. With this purpose, exosomes were isolated from raw bovine milk, combining ultracentrifugation and size exclusion chromatography (SEC) methodology. Isolated exosomes were then loaded with exogenous hsa-miR148a-3p, a highly expressed miRNA in milk exosomes. The suitability of exosomes as delivery vehicles for extracellular RNAs was tested by evaluating the absorption of miR-148a-3p in hepatic (HepG2) and intestinal (Caco-2) cell lines. The potential exertion of a biological effect by miR-148a-3p was assessed by gene expression analysis, using microarrays. Results support that bovine milk is a cost-effective source of exosomes which can be used as nanocarriers of functional miRNAs with a potential use in RNA-based therapy. In addition, we show here that a combination of ultracentrifugation and SEC technics improve exosome enrichment, purity, and integrity for subsequent use.

scholarly journals GAPDH controls extracellular vesicle biogenesis and enhances therapeutic potential of EVs in silencing the Huntingtin gene in mice via siRNA delivery

2020 ◽  
Author(s):  
Ghulam Hassan Dar ◽  
Cláudia C. Mendes ◽  
Wei-Li Kuan ◽  
Mariana Conceição ◽  
Samir El-Andaloussi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Sirna Delivery ◽  
Extracellular Vesicle ◽  
Glycolytic Enzyme ◽  
Target Cells ◽  
Binding Motif ◽  
Systemic Injection ◽  
The Brain

AbstractExtracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication and pathophysiology. Their capacity to transfer biomolecules between cells has sparked efforts to bioengineer EVs as drug delivery vehicles. However, a better understanding of EV biogenesis mechanisms and function is required to unleash their considerable therapeutic potential. Here we demonstrate a novel role for GAPDH, a glycolytic enzyme, in EV assembly and secretion, and we exploit these findings to develop a GAPDH-based methodology to load therapeutic siRNAs onto EVs for targeted drug delivery to the brain. In a series of experiments, we observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif, designated as G58, and discover that the tetrameric nature of GAPDH promotes extensive EV aggregation. Studies in a Drosophila EV biogenesis model demonstrate that GAPDH is absolutely required for normal generation of intraluminal vesicles in endosomal compartments and promotes vesicle clustering both inside and outside the cell. Fusing a GAPDH-derived G58 peptide to dsRNA-binding motifs permits highly efficient loading of RNA-based drugs such as siRNA onto the surface of EVs. Such vesicles efficiently deliver siRNA to target cells in vitro and into the brain of a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in multiple anatomical regions of the brain and modulation of phenotypic features of disease. Taken together, our study demonstrates a novel role for GAPDH in EV biogenesis, and that the presence of free GAPDH binding sites on EVs can be effectively exploited to substantially enhance the therapeutic potential of EV-mediated drug delivery to the brain.

scholarly journals Exosomes: Cell-Derived Nanoplatforms for the Delivery of Cancer Therapeutics

2020 ◽  
Vol 22 (1) ◽  
pp. 14
Author(s):  
Hyosuk Kim ◽  
Eun Hye Kim ◽  
Gijung Kwak ◽  
Sung-Gil Chi ◽  
Sun Hwa Kim ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Cancer Therapeutics ◽  
Strong Stability ◽  
Target Cells ◽  
Drug Delivery Vehicles ◽  
Exosome Biogenesis ◽  
Donor Cells ◽  
Delivery Vehicles ◽  
Targeting Ability

Exosomes are cell-secreted nanovesicles that naturally contain biomolecular cargoes such as lipids, proteins, and nucleic acids. Exosomes mediate intercellular communication, enabling the transfer biological signals from the donor cells to the recipient cells. Recently, exosomes are emerging as promising drug delivery vehicles due to their strong stability in blood circulation, high biocompatibility, low immunogenicity, and natural targeting ability. In particular, exosomes derived from specific types of cells can carry endogenous signaling molecules with therapeutic potential for cancer treatment, thus presenting a significant impact on targeted drug delivery and therapy. Furthermore, exosomes can be engineered to display targeting moieties on their surface or to load additional therapeutic agents. Therefore, a comprehensive understanding of exosome biogenesis and the development of efficient exosome engineering techniques will provide new avenues to establish convincing clinical therapeutic strategies based on exosomes. This review focuses on the therapeutic applications of exosomes derived from various cells and the exosome engineering technologies that enable the accurate delivery of various types of cargoes to target cells for cancer therapy.

scholarly journals Biodistribution and Pharmacokinectics of Liposomes and Exosomes in a Mouse Model of Sepsis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 427
Author(s):  
Amin Mirzaaghasi ◽  
Yunho Han ◽  
So-Hee Ahn ◽  
Chulhee Choi ◽  
Ji-Ho Park
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Hek293t Cell ◽  
Biological Properties ◽  
Context Analysis ◽  
Drug Delivery Vehicles ◽  
Delivery Vehicles ◽  
Diseased State ◽  
Sepsis And Septic Shock

Exosomes have attracted considerable attention as drug delivery vehicles because their biological properties can be utilized for selective delivery of therapeutic cargoes to disease sites. In this context, analysis of the in vivo behaviors of exosomes in a diseased state is required to maximize their therapeutic potential as drug delivery vehicles. In this study, we investigated biodistribution and pharmacokinetics of HEK293T cell-derived exosomes and PEGylated liposomes, their synthetic counterparts, into healthy and sepsis mice. We found that biodistribution and pharmacokinetics of exosomes were significantly affected by pathophysiological conditions of sepsis compared to those of liposomes. In the sepsis mice, a substantial number of exosomes were found in the lung after intravenous injection, and their prolonged blood residence was observed due to the liver dysfunction. However, liposomes did not show such sepsis-specific effects significantly. These results demonstrate that exosome-based therapeutics can be developed to manage sepsis and septic shock by virtue of their sepsis-specific in vivo behaviors.

scholarly journals Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

2020 ◽  
Author(s):  
Mariana Conceição ◽  
Laura Forcina ◽  
Oscar P. B. Wiklander ◽  
Dhanu Gupta ◽  
Joel Z. Nordin ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Signalling Pathway ◽  
Peptide Sequence ◽  
Target Cells ◽  
Dimerization Domain ◽  
Decoy Receptor ◽  
Stat3 Phosphorylation

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

scholarly journals Exosomes in Alzheimer’s Disease: From Being Pathological Players to Potential Diagnostics and Therapeutics

2021 ◽  
Vol 22 (19) ◽  
pp. 10794
Author(s):  
Hagar M. Soliman ◽  
Ghada A. Ghonaim ◽  
Shaza M. Gharib ◽  
Hitesh Chopra ◽  
Aya K. Farag ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Adverse Reactions ◽  
Extracellular Vesicle ◽  
Clinical Applications ◽  
Drug Delivery Vehicles ◽  
Pathophysiological Role ◽  
Delivery Vehicles

Exosomes (EXOs) were given attention as an extracellular vesicle (EV) with a pivotal pathophysiological role in the development of certain neurodegenerative disorders (NDD), such as Parkinson’s and Alzheimer’s disease (AD). EXOs have shown the potential to carry pathological and therapeutic cargo; thus, researchers have harnessed EXOs in drug delivery applications. EXOs have shown low immunogenicity as natural drug delivery vehicles, thus ensuring efficient drug delivery without causing significant adverse reactions. Recently, EXOs provided potential drug delivery opportunities in AD and promising future clinical applications with the diagnosis of NDD and were studied for their usefulness in disease detection and prediction prior to the emergence of symptoms. In the future, the microfluidics technique will play an essential role in isolating and detecting EXOs to diagnose AD before the development of advanced symptoms. This review is not reiterative literature but will discuss why EXOs have strong potential in treating AD and how they can be used as a tool to predict and diagnose this disorder.

scholarly journals Skimmed Bovine Milk-Derived Extracellular Vesicles Isolated via “Salting-Out”: Characterizations and Potential Functions as Nanocarriers

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiao-Hui Tan ◽  
Dong Fang ◽  
Yong-De Xu ◽  
Tie-Gui Nan ◽  
Wen-Peng Song ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Bovine Milk ◽  
Spherical Shape ◽  
Cost Effective ◽  
Great Promise ◽  
Salting Out ◽  
Marker Proteins ◽  
Icariside Ii ◽  
Delivery Vehicles ◽  
Endothelial Nitric Oxide

Bovine milk-derived extracellular vesicles (BM-EVs) are recognized as promising nanoscale delivery vectors owing to their large availability. However, few isolation methods can achieve high purity and yield simultaneously. Therefore, we developed a novel and cost-effective procedure to separate BM-EVs via “salting-out.” First, BM-EVs were isolated from skimmed milk using ammonium sulfate. The majority of BM-EVs were precipitated between 30 and 40% saturation and 34% had a relatively augmented purity. The separated BM-EVs showed a spherical shape with a diameter of 60–150 nm and expressed the marker proteins CD63, TSG101, and Hsp70. The purity and yield were comparable to the BM-EVs isolated via ultracentrifugation while ExoQuick failed to separate a relatively pure fraction of BM-EVs. The uptake of BM-EVs into endothelial cells was dose- and time-dependent without significant cytotoxicity. The levels of endothelial nitric oxide syntheses were regulated by BM-EVs loaded with icariside II and miRNA-155-5p, suggesting their functions as delivery vehicles. These findings have demonstrated that it is an efficient procedure to isolate BM-EVs via “salting-out,” holding great promise toward therapeutic applications.

scholarly journals Red Blood Cell Extracellular Vesicle-Based Drug Delivery: Challenges and Opportunities

2021 ◽  
Vol 8 ◽  
Author(s):  
Wararat Chiangjong ◽  
Pukkavadee Netsirisawan ◽  
Suradej Hongeng ◽  
Somchai Chutipongtanate
Keyword(s):  
Drug Delivery ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Large Scale ◽  
Regulatory Protein ◽  
Extracellular Vesicle ◽  
Clinical Applications ◽  
Target Cells ◽  
Scale Production ◽  
Advantages And Disadvantages

Recently, red blood cell-derived extracellular vesicles (RBCEVs) have attracted attention for clinical applications because of their safety and biocompatibility. RBCEVs can escape macrophages through the binding of CD47 to inhibitory receptor signal regulatory protein α. Furthermore, genetic materials such as siRNA, miRNA, mRNA, or single-stranded RNA can be encapsulated within RBCEVs and then released into target cells for precise treatment. However, their side effects, half-lives, target cell specificity, and limited large-scale production under good manufacturing practice remain challenging. In this review, we summarized the biogenesis and composition of RBCEVs, discussed the advantages and disadvantages of RBCEVs for drug delivery compared with synthetic nanovesicles and non-red blood cell-derived EVs, and provided perspectives for overcoming current limitations to the use of RBCEVs for clinical applications.

Therapeutic potential of essential oil based microemulsions: Reviewing state-of-the-art

2021 ◽  
Vol 18 ◽  
Author(s):  
Divya Thakur ◽  
Gurpreet Kaur ◽  
Ashana Puri ◽  
Rajat Nanda
Keyword(s):  
Drug Delivery ◽  
Essential Oil ◽  
Essential Oils ◽  
Therapeutic Potential ◽  
Microemulsion System ◽  
Active Components ◽  
Tea Tree ◽  
Drug Delivery Vehicles ◽  
Anti Oxidant ◽  
Delivery Vehicles

: A pre-eminent emulsion based micellar drug delivery system, “microemulsion”, comprising of drug in oil or water phase, stabilized by surfactants and co-surfactants, has been evidenced to have phenomenal role in number of applications. Oils play an important role in formation of ME and increase the drug absorption at the site of action. Oils employed in microemulsion formulation solubilize lipophilic drug. As concept of “natural” therapies is recently gaining importance amongst researchers all over the world, scientists are employing essential oil as an organic component in this system. The active components of essential oils include flavonoids, phenylpropanoids, monoterpenes and polyunsaturated of mega-6-fatty acids. These oils are enriched with characteristic intrinsic properties such as anti-oxidant, anti-bacterial, anti-viral, etc. bestows an enhanced supremacy to whole microemulsion system. This mini-review is the first to document various types of essential oils employed in microemulsion systems and highlight their therapeutic potential and applications as drug delivery vehicles. Key inferences from this study suggest: 1) Clove oil is the most explored oil for incorporation into microemulsion based system, followed by peppermint and Tea Tree Oil (TTO). 2) Penetration enhancing effects of these oils is due to the presence of terpenic constituents. 3) Essential oil based microemulsions protect volatility of ethereal oils and protect them from degradation in presence of light, air, temperature. 4) These systems may also be explored for their applications in different industries like aromatherapy, food, drink, fragrance, flavour, cosmeceutical, soap, petroleum and pharmaceutical industry.

scholarly journals Extracellular Vesicle-Based Therapeutics for Heart Repair

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 570
Author(s):  
Laura Saludas ◽  
Cláudia C. Oliveira ◽  
Carmen Roncal ◽  
Adrián Ruiz-Villalba ◽  
Felipe Prósper ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Cell Communication ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Cardiac Damage ◽  
Heterogeneous Membrane ◽  
Heart Repair

Extracellular vesicles (EVs) are constituted by a group of heterogeneous membrane vesicles secreted by most cell types that play a crucial role in cell–cell communication. In recent years, EVs have been postulated as a relevant novel therapeutic option for cardiovascular diseases, including myocardial infarction (MI), partially outperforming cell therapy. EVs may present several desirable features, such as no tumorigenicity, low immunogenic potential, high stability, and fine cardiac reparative efficacy. Furthermore, the natural origin of EVs makes them exceptional vehicles for drug delivery. EVs may overcome many of the limitations associated with current drug delivery systems (DDS), as they can travel long distances in body fluids, cross biological barriers, and deliver their cargo to recipient cells, among others. Here, we provide an overview of the most recent discoveries regarding the therapeutic potential of EVs for addressing cardiac damage after MI. In addition, we review the use of bioengineered EVs for targeted cardiac delivery and present some recent advances for exploiting EVs as DDS. Finally, we also discuss some of the most crucial aspects that should be addressed before a widespread translation to the clinical arena.

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