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Internalization of EVs. EVs are internalized into cells through macropinocytosis, clatherin or calveolin-mediated endocytosis, lipid raft-mediated endocytosis, fusion, and phagocytosis. EVs deliver their cargo (proteins, RNAs, and DNAs), which is released into the cytoplasm or ER. EV, extracellular vesicle; ER, endoplasmic reticulum. Figure created with BioRender.
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Extracellular vesicles (EVs) are small membrane-based nanovesicles naturally released from cells. Extracellular vesicles mimetics (EVMs) are artificial vesicles engineered from cells or in combination with lipid materials, and they mimic certain characteristics of EVs. As such, EVs facilitate intracellular communication by carrying and delivering b...
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... deliver biological materials, loaded drugs, or nucleic acids into recipient cells, EVs must navigate through the plasma membrane. EVs are internalized into cells by various ways, such as macropinocytosis, clatherin or calveolin-mediated endocytosis, phagocytosis, and lipid raftmediated and direct fusion ( Figure 4) [69,70]. EV internalization is generally reported as an active process that uses a single or a combination of classical endocytic pathways [20,21,46,71]. ...
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Osteoarthritis (OA) is a degenerative joint disease that is common among the middle-aged and older populations, causes patients to experience recurrent pain in their joints and negatively affects their quality of life. Currently, therapeutic options for patients with OA consist of medications to alleviate pain and treat the symptoms; however, due t...
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... To address the challenges associated with EVs, EVs mimicking nanovesicles (NVs) which have similar biophysical characteristics to EVs have been generated via durably extruding cells through a microfilter (223,224). EVs mimicking NVs are promising carriers which can be engineered to load with a variety of therapeutic drugs (225). Findings have demonstrated that melatonin-loaded EVs mimicking NVs effectively alleviated atopic dermatitis induced by 2,4-Dinitrofluorobenzene through the suppression of mast cell infiltration and local inflammation. ...
Osteoarthritis (OA) is a highly prevalent age-related musculoskeletal disorder that typically results in chronic pain and disability. OA is a multifactorial disease, with increased oxidative stress, dysregulated inflammatory response, and impaired matrix metabolism contributing to its onset and progression. The neurohormone melatonin, primarily synthesized by the pineal gland, has emerged as a promising therapeutic agent for OA due to its potential to alleviate inflammation, oxidative stress, and chondrocyte death with minimal adverse effects. The present review provides a comprehensive summary of the current understanding regarding melatonin as a promising pharmaceutical agent for the treatment of OA, along with an exploration of various delivery systems that can be utilized for melatonin administration. These findings may provide novel therapeutic strategies and targets for inhibiting the advancement of OA.
... While EVs possess favorable characteristics as nanocarriers-such as low immunogenicity, the capability to cross biological barriers, stable circulation, and organ targeting-there are significant challenges impeding their optimal use [4]. Issues related to safety, scalability, and the identification of compatible physicochemical attributes present limitations [5]. These challenges arise partly because the primary sources of nanocarrier EVs in research are immortalized cell lines, which raise concerns about human safety and resource availability [6]. ...
Extracellular vesicles (EVs) represent a complex mechanism of molecular exchange that has garnered significant attention in recent times. Nonetheless, identifying sustainable sources of biologically safe EVs remains challenging. This chapter delves into the utilization of fermented food industry by-products as a circular and secure reservoir of biocompatible EVs, dubbed as BP-EVs. BP-EVs demonstrate excellent oral bioavailability and biodistribution, with negligible cytotoxicity, and a preferential targeting capacity toward the central nervous system, liver, and skeletal tissues. The ease of editing BP-EVs is also depicted using the most common EV editing methods in this chapter. Globally, these groundbreaking findings are poised to unlock significant avenues for leveraging BP-EVs as an optimal source of biocompatible nanovesicles across a wide array of applications within the bioeconomy and biomedical fields. These applications primarily target molecule delivery into the central nervous system and skeletal tissue but are not limited to these two organism systems.
... Still, there are scalability and cost challenges. 9,10 There is a substantial interest in producing "forced" EVs, such as by using physical methods such as sonication, extrusion, or highpressure homogenization that disrupt cell membranes to release membrane vesicles. [9][10][11] Several groups explored chemically triggered release as an alternative to the aggressive energydependent physical disruption that may damage cellular proteins. ...
... 9,10 There is a substantial interest in producing "forced" EVs, such as by using physical methods such as sonication, extrusion, or highpressure homogenization that disrupt cell membranes to release membrane vesicles. [9][10][11] Several groups explored chemically triggered release as an alternative to the aggressive energydependent physical disruption that may damage cellular proteins. Thus, using high throughput screening of engineered cells that express nano luciferase-tetraspanin fusion, chemicals that can promote the formation of EV via stimulation of natural biogenesis have been discovered. ...
... [15][16][17][18] Moreover, hybrid EVs have been generated by fusion between lipids and pre-isolated EVs, with additional targeting and biological properties. 9,[19][20][21][22] We screened 13 cyanine lipid derivatives and 9 common non-cyanine lipid formulations for the efficiency of EV release from THP-1 monocytic cells. We confirmed the release by selected cyanine lipids from bioluminescent 4T1 breast cancer cells. ...
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Extracellular vesicles (EV) have garnered significant attention in the fields of drug delivery, imaging, and immunotherapy. There is a need in methods to enhance release of EVs from cells. We found that at high labeling concentrations (100µM), indocarbocyanine lipids DiD and DiR that are commonly used for labeling cells, nanoparticles and EVs, promoted shedding of cell membrane tetraspanins with concomitant release of EVs in the medium. To further investigate this phenomenon, we screened a library of lipids and liposomal formulations for the release of membrane marker CD63 from THP-1 cells, and membrane red nanolantern (RNL) from 4T1 cells. We found a strong dependency of the EV release on lipid structure. In general, lipids that had a cyanine headgroup were more efficient than PEGylated phospholipids, neutral and cationic liposomes, with some lipids enhancing the release of CD63 up to 4-fold, and of RNL up to 8-fold, over vehicle treated control. A side-by-side comparison of cyanine lipid derivatives and corresponding precursor lipids confirmed that the cyanine headgroup significantly promoted shedding of RNL. Mutation of an exosome biogenesis regulator UNC13D did not hinder the release. Lipid-released EV could be modified with anti-interleukin 13 receptor alpha 2 antibody and targeted to glioma cells, suggesting potential utility in drug delivery. Furthermore, the impact of extraneously added lipids on cell membrane integrity should be carefully considered in cell labeling and drug delivery applications.
... Targeting peptides can be anchored on the EV surface by attaching to the phospholipids or other ligands on the EV surface [197], or by modifying the EV surface using different strategies such as covalent modification, namely click chemistry or non-covalent modification (electrostatic interaction, hydrophobic interaction, aptamer-based modification, etc.) [198][199][200]. Several methods such as electroporation, sonication, freeze-thaw cycles, and membrane permeabilization using chemical agents can be used to incorporate biological or chemical cargo in EVs [201][202][203][204]. ...
Extracellular vesicles (EVs) are critical mediators of cell communication, playing important roles in regulating molecular cross-talk between different metabolic tissues and influencing insulin sensitivity in both healthy and gestational diabetes mellitus (GDM) pregnancies. The ability of EVs to transfer molecular cargo between cells imbues them with potential as therapeutic agents. During pregnancy, the placenta assumes a vital role in metabolic regulation, with multiple mechanisms of placenta-mediated EV cross-talk serving as central components in GDM pathophysiology. This review focuses on the role of the placenta in the pathophysiology of GDM and explores the possibilities and prospects of targeting the placenta to address insulin resistance and placental dysfunction in GDM. Additionally, we propose the use of EVs as a novel method for targeted therapeutics in treating the dysfunctional placenta. The primary aim of this review is to comprehend the current status of EV targeting approaches and assess the potential application of these strategies in placental therapeutics, thereby delivering molecular cargo and improving maternal and fetal outcomes in GDM. We propose that EVs have the potential to revolutionize GDM management, offering hope for enhanced maternal-fetal health outcomes and more effective treatments.
... Lipid layer has been not only recognized as a bioreagent carrier but also as a bio-membrane model [9][10][11][12][13][14][15]. The layers have either one (called mono-) or two (bi-) layers, which have spherical and planar shapes [16][17][18][19]. ...
Gastric-lipase (GL) binding to a lipid layer was investigated for the phase of the layer adjusted with the ratio of stigmasterol to the lipid using surface plasmon resonance. While the layer was formed on the hydrophobic surface, more stigmasterol led to lower surface density only in the dipalmitoylphosphatidylcholine (DPPC) layer. The addition of stigmasterol was believed to transform the phase (condensed liquid-phase) of DPPC layer closer to the phase (expanded liquid-phase) of dioleoylphosphatidylcholine (DOPC) layer. At a ratio greater than 15:85, the effect of the stigmasterol on the DPPC was saturated. The adsorption behavior of GL showed the similar trend with the lipid formation. The adsorption increased with the increase in the ratio of stigmasterol to lipid up to 15:85. On the DOPC layer of the expanded liquid-phase, the most adsorption seemed to occur and was indistinguishable from that in the DPPC layer of 15:85. The surface density of the adsorbed GL was interpreted into the fraction of the stigmasterol-dependent DPPC, 0.33, 0.67, and 1.00 for 10:90, 5:95, and 0:100 of DPPC. Furthermore, the equilibrium constant was between 1 × 10 ¹³ M ⁻¹ and 2 × 10 ¹³ M ⁻¹ and the kinetics of the adsorption showed an increase in the adsorption rate constant with the increase of the ratio up to 15:85.
... There is an EV that is not involved in physiological mechanisms in the body and is artificially produced in vitro [110]. It is a type of nanovesicle that can be designed using any cell type or produced through fusion with prerequisite materials such as liposomes [177]. The production method is to use nanosized filters with reduced pore size to continuously compress and decompose cells, and separate them from the interface between the 10-50% iodixanol layers through a two-step density gradient ultracentrifugation [178]. ...
With their seemingly limitless capacity for self-improvement, stem cells have a wide range of potential uses in the medical field. Stem-cell-secreted extracellular vesicles (EVs), as paracrine components of stem cells, are natural nanoscale particles that transport a variety of biological molecules and facilitate cell-to-cell communication which have been also widely used for targeted drug delivery. These nanocarriers exhibit inherent advantages, such as strong cell or tissue targeting and low immunogenicity, which synthetic nanocarriers lack. However, despite the tremendous therapeutic potential of stem cells and EVs, their further clinical application is still limited by low yield and a lack of standardized isolation and purification protocols. In recent years, inspired by the concept of biomimetics, a new approach to biomimetic nanocarriers for drug delivery has been developed through combining nanotechnology and bioengineering. This article reviews the application of biomimetic nanocarriers derived from stem cells and their EVs in targeted drug delivery and discusses their advantages and challenges in order to stimulate future research.
... This component of EV does not increase the likelihood of tumor growth. EVs are nano-sized vesicles that can enter tissues and even cells, as well as traverse the blood-brain barrier more easily than cells [102,121,122]. EVs can elude the immune system and, like cells, they have a negative zeta potential for extended circulation [123]. ...
Globally, neurological diseases pose a major burden to healthcare professionals in terms of the management and prevention of the disorder. Among neurological diseases, Alzheimer’s disease (AD) accounts for 50%–70% of dementia and is the fifth leading cause of mortality worldwide. AD is a progressive, degenerative neurological disease, with the loss of neurons and synapses in the cerebral cortex and subcortical regions. The management of AD remains a debate among physicians as no standard and specific “disease-modifying” modality is available. The concept of ‘Regenerative Medicine’ is aimed at regenerating the degenerated neural tissues to reverse the pathology in AD. Genetically modified engineered stem cells modify the course of AD after transplantation into the brain. Extracellular vesicles (EVs) are an emerging new approach in cell communication that involves the transfer of cellular materials from parental cells to recipient cells, resulting in changes at the molecular and signaling levels in the recipient cells. EVs are a type of vesicle that can be transported between cells. Many have proposed that EVs produced from mesenchymal stem cells (MSCs) may have therapeutic promise in the treatment of AD. The biology of AD, as well as the potential applications of stem cells and their derived EVs-based therapy, were explored in this paper.
... Although these achievements have garnered significant scientific and clinical attention, there are certain barriers that limit their clinical translation. Two of the biggest challenges include scaling up EV production and the enhancement of the drug-loading capacity [17][18][19]. Several methods for the efficient production of EVs have been developed, including cytochalasin B-induced EVs, microfluidic fabrication, and serial extrusion through filters with decreasing pore sizes [20]. ...
Spinal cord injury (SCI) remains one of the current medical and social problems, as it causes deep disability in patients. The use of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) is one strategy for stimulating the post-traumatic recovery of the structure and function of the spinal cord. Here, we chose an optimal method for obtaining cytochalasin B-induced EVs, including steps with active vortex mixing for 60 s and subsequent filtration to remove nuclei and disorganized inclusions. The therapeutic potential of repeated intrathecal injection of autologous MSC-derived EVs in the subacute period of pig contused SCI was also evaluated for the first time. In this study, we observed the partial restoration of locomotor activity by stimulating the remyelination of axons and timely reperfusion of nervous tissue.
... The lipid composition of exosomal membranes not only enables them to fuse directly with the plasma membranes of recipient cells, but also increases the physicochemical stability of exosomes in the extracellular environment [28]. This protects the exosomal cargo from degradation to ensure its integrity until it is distributed to target cells [18,47]. ...
... In addition to their protein and lipid compositions, exosomes are carriers of a wide range of genetic materials that can be transmitted to neighboring and distant cells. These genetic materials include RNA molecules [e.g., messenger RNA (mRNA) and microRNA (miRNA)] and deoxyribonucleic acid (DNA) molecules (e.g., mitochondrial DNA and chromosomal DNA) [18,47,48]. Exosomal components and their main biofunctions are summarized in Table 1 [32,34,39,40,43,44,[47][48][49][50][51][52][53]. ...
... These genetic materials include RNA molecules [e.g., messenger RNA (mRNA) and microRNA (miRNA)] and deoxyribonucleic acid (DNA) molecules (e.g., mitochondrial DNA and chromosomal DNA) [18,47,48]. Exosomal components and their main biofunctions are summarized in Table 1 [32,34,39,40,43,44,[47][48][49][50][51][52][53]. ...
A bio-inspired strategy has recently been developed for camouflaging nanocarriers with biomembranes, such as natural cell membranes or subcellular structure-derived membranes. This strategy endows cloaked nanomaterials with improved interfacial properties, superior cell targeting, immune evasion potential, and prolonged duration of systemic circulation. Here, we summarize recent advances in the production and application of exosomal membrane-coated nanomaterials. The structure, properties, and manner in which exosomes communicate with cells are first reviewed. This is followed by a discussion of the types of exosomes and their fabrication methods. We then discuss the applications of biomimetic exosomes and membrane-cloaked nanocarriers in tissue engineering, regenerative medicine, imaging, and the treatment of neurodegenerative diseases. Finally, we appraise the current challenges associated with the clinical translation of biomimetic exosomal-membrane-surface-engineered nanovehicles and evaluate the future of this technology.
... 46,51,52 When multivesicular bodies fuse with the plasma membrane, exosomes are released into the extracellular space, which can then be taken up by the recipient cells and dictate changes in cellular phenotypes and behaviors. [53][54][55] This is due to their ability to activate/inhibit certain signaling pathways, or trigger changes in gene expression or protein translation. There are three different ways that exosomes potentially enter cells: directly fusing with the cell membrane, interacting with cell surface receptors (ligand-receptor interactions), and uptake of exosomes through endocytosis, which includes caveolin-mediated endocytosis, clathrin-mediated endocytosis, lipid-raftmediated endocytosis, phagocytosis, and macropinocytosis. ...
Bio-mimicking principles have recently been proposed for the surface functionalization of nanoparticles (NPs). Such a strategy is based on camouflaging the NP surface with functional biomembranes to render superior biocompatibility, interfacial features, immune evasion, and active targeting properties to nanomaterials. In this area of research, cell membranes derived from a plethora of highly optimized cells, such as red blood cells, immune cells, platelets, stem cells, cancer cells, and others, have been the pioneers as coating materials. This biomimetic concept has then been applied to subcellular structures, namely extracellular vesicles and intracellular organelles. Exosomes are a nanosized extracellular vesicle subtype secreted by most cells. These phospholipid bilayer nanovesicles are surface enriched with proteins accounting for their dynamic and prominent roles in immune escape, cell-cell communication, and specific cell uptake. Their intrinsic stability, biocompatibility, reduced immunogenicity and toxicity, and specific cell-targeting features denote an optimal biological nanocarrier for biomedical applications. This review highlights the current clinical applications of exosome membrane-coated nanosystems in cancer diagnosis and therapy. These biomimetic nanosystems have emerged as a promising avenue to provide effective, highly specific, and safer cancer-targeted applications. Finally, challenges hindering their clinical application will be mentioned.
