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![FG@PEL-based PTT for inhibiting tumor progression and lung metastasis in a 4T1 primary tumor mouse model in vivo. a Schematic diagram of FG@PEL-based PTT for inhibiting tumor progression in an H22 primary model. b–c Tumor volumes H22 tumor-bearing mice after different treatments. d Immunofluorescence assay examining the expression of GPX-4 in tumor tissues isolated from the aforementioned mice. Scale bar: 100 μm. e–f Levels of ATP, HMGB1, calreticulin, and eif-2a. g Lungs excised from 4T1 orthotopic tumor mouse models were used to evaluate the inhibitory effect of different treatments on pulmonary metastasis. H&E staining was performed on whole lungs isolated from these mice. Scale bar: 2000 μm. H&E staining of partial lung tissue. Scale bar: 100 μm.
Reprinted with permission from Ref [184]](publication/372487020/figure/fig7/AS:11431281175801408@1689906534959/FGPEL-based-PTT-for-inhibiting-tumor-progression-and-lung-metastasis-in-a-4T1-primary.png)
FG@PEL-based PTT for inhibiting tumor progression and lung metastasis in a 4T1 primary tumor mouse model in vivo. a Schematic diagram of FG@PEL-based PTT for inhibiting tumor progression in an H22 primary model. b–c Tumor volumes H22 tumor-bearing mice after different treatments. d Immunofluorescence assay examining the expression of GPX-4 in tumor tissues isolated from the aforementioned mice. Scale bar: 100 μm. e–f Levels of ATP, HMGB1, calreticulin, and eif-2a. g Lungs excised from 4T1 orthotopic tumor mouse models were used to evaluate the inhibitory effect of different treatments on pulmonary metastasis. H&E staining was performed on whole lungs isolated from these mice. Scale bar: 2000 μm. H&E staining of partial lung tissue. Scale bar: 100 μm. Reprinted with permission from Ref [184]
Source publication
Extracellular vesicles (EVs) are nano-sized, natural, cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. Thus, they can serve as natural carriers for therapeutic agents and drugs, and have many advantages over conventional nanocarriers, including their low immunogenicity, good biocompatibility, na...
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Citations
... Interestingly, ARHGDIA and Cofilin 1 were only expressed in this compartment, not in lEVs. Considering the functional role of the studied proteins and the endosomal endocytic biogenesis of sEVs [33], this finding suggests an inflammatory dysregulation in membrane trafficking, resulting in the proinflammatory release of small vesicles on the target organ. Secondly, we noted significant differences between MS patients and HCs in the protein expression of both large and small vesicles. ...
Growing evidence identifies extracellular vesicles (EVs) as important cell-to-cell signal transducers in autoimmune disorders, including multiple sclerosis (MS). If the etiology of MS still remains unknown, its molecular physiology has been well studied, indicating peripheral blood mononuclear cells (PBMCs) as the main pathologically relevant contributors to the disease and to neuroinflammation. Recently, several studies have suggested the involvement of EVs as key mediators of neuroimmune crosstalk in central nervous system (CNS) autoimmunity. To assess the role of EVs in MS, we applied electron microscopy (EM) techniques and Western blot analysis to study the morphology and content of plasma-derived EVs as well as the ultrastructure of PBMCs, considering four MS patients and four healthy controls. Through its exploratory nature, our study was able to detect significant differences between groups. Pseudopods and large vesicles were more numerous at the plasmalemma interface of cases, as were endoplasmic vesicles, resulting in an activated aspect of the PBMCs. Moreover, PBMCs from MS patients also showed an increased number of multivesicular bodies within the cytoplasm and amorphous material around the vesicles. In addition, we observed a high number of plasma-membrane-covered extensions, with multiple associated large vesicles and numerous autophagosomal vacuoles containing undigested cytoplasmic material. Finally, the study of EV cargo evidenced a number of dysregulated molecules in MS patients, including GANAB, IFI35, Cortactin, Septin 2, Cofilin 1, and ARHGDIA, that serve as inflammatory signals in a context of altered vesicular dynamics. We concluded that EM coupled with Western blot analysis applied to PBMCs and vesiculation can enhance our knowledge in the physiopathology of MS.
... By the term "extracellular vesicles" (EVs), according to the currently accepted nomenclature, we mean heterogeneous vesicles of cellular origin, surrounded by a lipid bilayer, incapable of self-replication (not containing a functional nucleus), and which are produced by most cells through various mechanisms [1]. So far, EVs have been detected in plants [2][3][4], bacteria [5][6][7][8], fungi [6,9], in vitro cultures of eukaryotic cells, and biological samples obtained from humans and animals [10][11][12][13]. Established in 2011, the International Society of Extracellular Vesicles (ISEV) has updated the EV nomenclature. ...
Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management.
... 11 For instance: delivery of siRNA and other chemotherapeutics by lipid nanoparticles or EV based therapeutic delivery is limited by endosomal entrapment. 12,13 This unfortunate fate can render potentially life-saving medications ineffective. 12 Consequently, there is an urgent need to develop widely applicable technologies that can modulate and precisely control the trafficking of drug, molecules, and nanoparticles within cells. ...
Chemotherapy resistance and endosomal entrapment, controlled by intracellular trafficking processes, is a major factor in treatment failure. Here, we test the hypothesis that external electrical stimulus can be used to modulate intracellular trafficking of chemotherapeutic drugs in most common malignant brain tumors in childhood (medulloblastoma) and gold nanoparticles (GNPs) in adulthood (glioblastoma). We demonstrate that application of alternating current (AC) with frequencies ranging from KHz-MHz and low strength (1V/cm) lead to killing of cisplatin and vincristine resistant (mediated by extracellular vesicles) medulloblastoma cell lines. On the other hand, in primary glioblastoma cells, high frequency AC (MHz) regulated the endosomal escape of GNPs. No significant effect on the viability of the control medulloblastoma cells (resistant cells cultured in drug free media and non-resistant cells) and glioblastoma cells after AC treatment confirmed targeting of intracellular trafficking process. This work supports future application of AC in drug delivery and brain cancer therapy.
... The main methods for loading cargo into EVs can be divided into two broad categories: cell-based loading and non-cell-based loading. (i) Cell-based loading methods: Passive incubation: Small molecule drugs such as doxorubicin and curcumin can be loaded into EVs through simple incubation, though the loading efficiency is relatively low [53,54]. Transfection: Biomolecules such as small RNAs, mRNA, DNA, and proteins can be loaded into EVs through transfection. ...
... This method can achieve higher loading efficiency but requires transfection reagents, which may affect EV properties. (ii) Non-cell-based loading methods: Passive incubation: Similar to the cell-based approach, small molecule drugs can be loaded through simple incubation, but again with low efficiency [53,54]. Transfection: miRNAs and siRNAs can be loaded into isolated EVs through transfection, achieving enhanced efficiency but potentially altering EV structure and properties. ...
... However, challenges remain in achieving high loading efficiency without compromising EV integrity and cargo functionality. A variety of pharmaceutical ingredients and biomolecular cargo have been successfully loaded into EVs using these different methods, including small molecule drugs, nucleic acids, and proteins [53][54][55][56]. ...
Mesenchymal stem cells (MSCs) have emerged as a promising approach for drug delivery strategies because of their unique properties. These strategies include stem cell membrane-coated nanoparticles, stem cell-derived extracellular vesicles, immunomodulatory effects, stem cell-laden scaffolds, and scaffold-free stem cell sheets. MSCs offer advantages such as low immunogenicity, homing ability, and tumor tropism, making them ideal for targeted drug delivery systems. Stem cell-derived extracellular vesicles have gained attention for their immune properties and tumor-homing abilities, presenting a potential solution for drug delivery challenges. The relationship between MSC-based drug delivery and the self-renewal and differentiation capabilities of MSCs lies in the potential of engineered MSCs to serve as effective carriers for therapeutic agents while maintaining their intrinsic properties. MSCs exhibit potent immunosuppressive functions in MSC-based drug delivery strategies. Stem cell-derived EVs have low immunogenicity and strong therapeutic potential for tissue repair and regeneration. Scaffold-free stem cell sheets represent a cutting-edge approach in regenerative medicine, offering a versatile platform for tissue engineering and regeneration across different medical specialties. MSCs have shown great potential for clinical applications in regenerative medicine because of their ability to differentiate into various cell types, secrete bioactive factors, and modulate immune responses. Researchers are exploring these innovative approaches to enhance drug delivery efficiency and effectiveness in treating various diseases.
... Notably, previous research and our sequencing analysis revealed that suppression of SMC phenotypic switching-related genetic content was most significantly increased in serum-exos from patients with stable plaques (SPs) compared to those from patients with vulnerable plaques [14][15][16][17] , suggesting that the principal function of serum exosomes containing pertinent genetic content from SPs might be to regulate SMC phenotypic switching. Serum-exos are characterized by biocompatibility, low immunogenicity, and minimal adverse reactions 18,19 . Owing to these unique capabilities, serum-exos can serve as an easily clinically translatable medium for delivering genetic contents to patients for disease treatment without the adverse effects of gene editing. ...
Introduction
The function of serum-derived exosomes (serum-exos) that suppress smooth muscle cell (SMC) phenotypic switching-related genes in plaque stabilization is unclear. We aimed to determine the functional role of serum-exos, which are pivotal molecular regulators, in plaque stabilization and the underlying mechanism.
Methods and results
RNA sequencing and bioinformatic analyses of human serum-exos were used to identify circENC1, which is involved in SMC phenotypic switching and plaque stabilization. qRT‒PCR assays further confirmed that the circENC1 level was substantially lower in the unstable plaque (UP)-exo group than in the stable plaque (SP)-exo group. In mice treated with serum-exos from patients with SPs, the expression of the SMC contractile phenotype indicators ACTA2 and SM22 and the plaque stability increased. In contrast, in the group treated with serum-exos from patients with UPs, CD68 expression and the vulnerability index were increased. Moreover, circENC1 expression was negatively correlated with the plaque vulnerability index in the UP-exo group and the sham group. Mechanistically, single-cell analysis, chromatin isolation by RNA purification (ChIRP) and dual-luciferase reporter assays indicated that circENC1 suppressed SMC phenotypic switching by inhibiting the degradation of MYH9 and acting as a miR-513a-5p sponge to release MYOCD.
Conclusion
Serum exosomal circENC1 inhibits SMC phenotypic switching to stabilize plaques by binding to miR-513a-5p and inhibiting MYH9 degradation, indicating that this molecule may play an important role in the clinical diagnosis and treatment of atherosclerotic plaques.
... Interestingly, consistent with the fact that exosomes can be used as drug delivery systems [39][40][41][42], we discovered that exosomes derived from RWPE-1 cells could serve as an effective delivery system for miR-203a-3p antagomirs in a mouse model of chronic prostatitis. Moreover, we confirmed that exosomes derived from RWPE-1 cells have an optimal targeting ability for the prostate, compared with exosomes derived from mouse prostate tissues, the prostatic fluid of CP/CPPS-A patients, and the prostatic fluid of healthy individuals. ...
Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.
... These innovative perspectives extend to the treatment of GIDs, capitalizing on EVs capability to cross physiological barriers and deliver therapeutic payloads to the target tissues. In contrast to synthetic nanoparticles, which often provoke adverse immunological reactions such as cytokine release syndrome, cross-reactivity with endogenous proteins, anaphylaxis, the neutralization of biological activity, and non-acute immune responses, EVs derived from both human and non-human cells are distinguished by their high biocompatibility, stability, very low immunogenicity, and overall safety profile [21][22][23]. These findings support the idea of utilizing EVs as drug carriers, emphasizing their potential safety and biocompatibility. ...
Extracellular vesicles (EVs), acting as inherent nanocarriers adept at transporting a range of different biological molecules such as proteins, lipids, and genetic material, exhibit diverse functions within the gastroenteric tract. In states of normal health, they participate in the upkeep of systemic and organ homeostasis. Conversely, in pathological conditions, they significantly contribute to the pathogenesis of gastrointestinal diseases (GIDs). Isolating EVs from patients’ biofluids facilitates the discovery of new biomarkers that have the potential to offer a rapid, cost-effective, and non-invasive method for diagnosing and prognosing specific GIDs. Furthermore, EVs demonstrate considerable therapeutic potential as naturally targeted physiological carriers for the intercellular delivery of therapeutic cargo molecules or as nanoscale tools engineered specifically to regulate physio-pathological conditions or disease progression. Their attributes including safety, high permeability, stability, biocompatibility, low immunogenicity, and homing/tropism capabilities contribute to their promising clinical therapeutic applications. This review will delve into various examples of EVs serving as biomarkers or nanocarriers for therapeutic cargo in the context of GIDs, highlighting their clinical potential for both functional and structural gastrointestinal conditions. The versatile and advantageous properties of EVs position them as promising candidates for innovative therapeutic strategies in advancing personalized medicine approaches tailored to the gastroenteric tract, addressing both functional and structural GIDs.
... Therefore, the International Society for Extracellular Vesicles (ISEV) recommends the use of "extracellular vesicles" as a generic name for vesicles released by cells [63]. According to the size of the vesicle diameter, EVs can be roughly divided into exosomes, microvesicles, and apoptotic vesicles [27]. Exosomes are small EVs with a diameter of approximately 50-150 nm. ...
... The low density, small size, and wide distribution of EVs in the complex bodily fluid environment pose a considerable challenge for researchers to obtain high-purity EVs. Currently, the methods for isolating EVs are diverse, including ultracentrifugation, size exclusion chromatography, ultrafiltration, field flow fractionation, and precipitation [27]. Therefore, the identification of a unified and efficient isolation method is conducive to the uniformity of EV research and the large-scale production of EVs. ...
Ischemic stroke is a fatal and disabling disease worldwide and imposes a significant burden on society. At present, biological markers that can be conveniently measured in body fluids are lacking for the diagnosis of ischemic stroke, and there are no effective treatment methods to improve neurological function after ischemic stroke. Therefore, new ways of diagnosing and treating ischemic stroke are urgently needed. The neurovascular unit, composed of neurons, astrocytes, microglia, and other components, plays a crucial role in the onset and progression of ischemic stroke. Extracellular vesicles are nanoscale lipid bilayer vesicles secreted by various cells. The key role of extracellular vesicles, which can be released by cells in the neurovascular unit and serve as significant facilitators of cellular communication, in ischemic stroke has been extensively documented in recent literature. Here, we highlight the role of neurovascular unit-derived extracellular vesicles in the diagnosis and treatment of ischemic stroke, the current status of extracellular vesicle engineering for ischemic stroke treatment, and the problems encountered in the clinical translation of extracellular vesicle therapies. Extracellular vesicles derived from the neurovascular unit could provide an important contribution to diagnostic and therapeutic tools in the future, and more studies in this area should be carried out.
... After drug loading, the sizes and loads of extracellular vesicles change, and these changes tend to increase depending on drug loading. The type of loaded drug molecules causes this change and varies depending on the amount of retention of drugs in extracellular vesicles [33,49,[52][53][54][55]. Consequently, the excess binding of PTX, a hydrophobic drug, contributed to the size increase. ...
Microfluidic devices, renowned for their microscale fluid control capabilities, offer efficient extracellular vesicle (EV) purification. This study aimed to pioneer the development of a Lab-on-Chip (LOC) system for the simultaneous isolation and drug loading of EVs from serum, harnessing their innate carrier properties. The microfluidic system consists of surface acoustic wave (SAW)-based isolation and miniaturized electroporation modules. EVs sourced from human serum and MDA-MB-231 cells were isolated via both ultracentrifugation and the microfluidic system and underwent comprehensive characterization, including size and quantity assessment using zeta-sizer, transmission electron microscopy (TEM), and flow cytometry. The apoptotic activity of paclitaxel (PTX)-loaded small EV was evaluated on MCF-10A and MDA-MB-231 cells. While the binding values of CD9, CD63, and CD81 on EVs isolated through ultracentrifugation and microfluidic remained similar, significant differences emerged in their drug loading capacities. Notably, PTX-loaded EVs obtained via the microfluidic system exhibited enhanced stability and faster cellular uptake, attributed to their narrower size distribution. The microfluidic system developed in this study demonstrates its utility for efficient small EV separation, marking a significant step in the field of EV-based drug delivery.
... Several mechanisms and substances are involved in the release of EVs, including the ESCRT complex, tetraspanin, neutral sphingomyelinase 2, phospholipid relocalisation and actin cytoskeleton depolymerisation [26][27][28][29][30]. Extracellular vesicles can be broadly classified into three groups: exosomes, microvesicles and apoptotic vesicles. In addition, oncosomes has also been identified [31]. Extensive research has demonstrated the benefits of using extracellular vesicles in disease diagnosis and treatment [17][18][19]. ...
Currently, stem cells are a prominent focus of regenerative engineering research. However, due to the limitations of commonly used stem cell sources, their application in therapy is often restricted to the experimental stage and constrained by ethical considerations. In contrast, urine-derived stem cells (USCs) offer promising advantages for clinical trials and applications. The noninvasive nature of the collection process allows for repeated retrieval within a short period, making it a more feasible option. Moreover, studies have shown that USCs have a protective effect on organs, promoting vascular regeneration, inhibiting oxidative stress, and reducing inflammation in various acute and chronic organ dysfunctions. The application of USCs has also been enhanced by advancements in biomaterials technology, enabling better targeting and controlled release capabilities. This review aims to summarize the current state of research on USCs, providing insights for future applications in basic and clinical settings.
