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Biomedicines
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Extracellular Vesicles and Exosomes as Therapeutic Agents
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Extracellular Vesicles and Exosomes as Therapeutic Agents

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 22715

Special Issue Editor

Dr. David J. Rademacher

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Guest Editor
Stritch School of Medicine, Core Microscopy Facility and Department of Microbiology and Immunology, Loyola University Chicago, Chicago, IL USA
Interests: neurodegenerative disease; addiction; microscopy; senescence; therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are lipid-bound vesicles secreted by cells into the extracellular space. The three main subtypes of EVs—microvesicles, exosomes, and apoptotic bodies—are differentiated based on their biogenesis, release pathway, size, content, and function. The content or “cargo” of EVs include nucleic acids, lipids, proteins, and metabolites. The role of EVs in cell–cell communication and their ability to act as carriers of biomarkers for diseases are well-established. EVs are widely considered as promising therapeutic options because they have a long circulating half-life, are tolerated well by the human body, are capable of penetrating cell membranes and targeting specific cell types, and have the capacity to be engineered. Indeed, the use of EVs (predominantly exosomes) as therapeutic agents and/or drug-delivery systems in neurodegenerative diseases, cancers, stroke, myocardial infarction, and several other pathologies has been the subject of intense research. Despite recent advances, a better understanding of the mechanisms by which EVs function would help unlock the full potential of EV-based therapeutics. This Special Issue welcomes articles focused on the use of EVs—including exosomes—as therapeutic agents, with a focus on articles that provide a better understanding of the uptake, biodistribution, and trafficking of EVs or elucidate the mechanisms by which EVs exert their therapeutic effects.

Dr. David J. Rademacher
Guest Editor

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Keywords

  • extracellular vesicles
  • exosomes
  • therapeutics
  • drug delivery
  • bioengineering

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Published Papers (9 papers)

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Research

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18 pages, 6624 KiB  
Article
Lyophilized Small Extracellular Vesicles (sEVs) Derived from Human Adipose Stem Cells Maintain Efficacy to Promote Healing in Neuronal Injuries
by Brianna Jones, Rekha Patel, Bangmei Wang, Theresa Evans-Nguyen and Niketa A. Patel
Biomedicines 2025, 13(2), 275; https://doi.org/10.3390/biomedicines13020275 - 23 Jan 2025
Cited by 1 | Viewed by 1145
Abstract
Background: Traumatic brain injury (TBI) occurs in individuals of all ages, predominantly during sports, accidents, and in active military service members. Chronic consequences of TBI include declined cognitive and motor function, dementia, and emotional distress. Small extracellular vesicles (sEVs), previously referred to as [...] Read more.
Background: Traumatic brain injury (TBI) occurs in individuals of all ages, predominantly during sports, accidents, and in active military service members. Chronic consequences of TBI include declined cognitive and motor function, dementia, and emotional distress. Small extracellular vesicles (sEVs), previously referred to as exosomes, are nano-sized lipid vesicles that play a role in intercellular communication. Our prior research established the efficacy of sEVs derived from human adipose stem cells (hASC sEVs) in accelerating the healing of brain injuries. The hASC sEVs are a biologic therapeutic and need to be stored at −20 °C or −80 °C. This limits their use in translating to everyday use in clinics or their inclusion in first-aid kits for application immediately after injury. To address this, here we demonstrate that hASC sEVs can be stored at room temperature (RT) for two months post lyophilization. Methods: A transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA) were used to validate the morphology of lyophilized RT sEVs. Using in vitro models of neuronal injury mimicking physical injury, inflammation, and oxidative stress, we demonstrate that lyophilized RT hASC sEVs are viable and promote the healing of neuronal injuries. Results: The lyophilized sEVs maintain their purity, size, and morphology upon rehydration. Lyophilized, RT stored sEVs showed better efficacy after two months compared with −80 °C stored sEVs. Conclusions: RT storage of lyophilized hASC sEVs maintains their efficacy to accelerate the healing of injuries in neuronal cells. This will advance the use of hASC sEVs, bringing them closer to use in clinics, home first-aid kits, and on battlefields by active service members. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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14 pages, 3680 KiB  
Article
Grapefruit-Derived Vesicles Loaded with Recombinant HSP70 Activate Antitumor Immunity in Colon Cancer In Vitro and In Vivo
by Luiza Garaeva, Elena Komarova, Svetlana Emelianova, Elena Putevich, Andrey L. Konevega, Boris Margulis, Irina Guzhova and Tatiana Shtam
Biomedicines 2024, 12(12), 2759; https://doi.org/10.3390/biomedicines12122759 - 3 Dec 2024
Viewed by 1312
Abstract
Background/Objectives: Stress protein HSP70 administered exogenously has demonstrated high potential as an efficient adjuvant in antitumor immune response. To enhance the antigen-presenting activity, bioavailability, and stability of exogenous recombinant human HSP70, we propose incorporating it into plant extracellular vesicles. Earlier, we found that [...] Read more.
Background/Objectives: Stress protein HSP70 administered exogenously has demonstrated high potential as an efficient adjuvant in antitumor immune response. To enhance the antigen-presenting activity, bioavailability, and stability of exogenous recombinant human HSP70, we propose incorporating it into plant extracellular vesicles. Earlier, we found that grapefruit-derived extracellular vesicles (GEV) were able to store the protein with no loss of its major function, chaperone activity. Methods: In this study, we tested whether HSP70 loaded into GEV (GEV-HSP70) could elicit an antitumor immune response in cellular and animal models of colorectal cancer. Results: To test the hypothesis in vitro, human and mouse colorectal cancer cell lines were used. We have shown that the addition of HSP70, either in free form or as part of GEVs, increases the sensitivity of human (HCT-116, DLD1) or mouse (CT-26) colon cancer cells to mouse cytotoxic lymphocytes and human NK-92 cells. Moreover, the amount of protein in the form of GEV-HSP70 required to cause the same activation of antitumor immunity was 20 times less than when HSP70 was added in free form. In a colon carcinoma model in vivo, GEV-HSP70 were inoculated subcutaneously into BALB/c mice together with CT-26 cells to form a tumor node. As compared with the control groups, we observed an increase in the lifespan of animals and a decrease in the tumor size, as well as a decrease in the level of TGFB1 IL-10 factors in the blood plasma. In vitro analysis of the immunomodulatory activity of GEV-HSP70 showed that antitumor response in GEV-HSP70-treated mice was associated with the accumulation of CD8+ cells. Conclusions: These results demonstrate the high feasibility and efficacy of the new technique based on HSP70 encapsulated in plant vesicles in activation of the specific response to colon tumors. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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16 pages, 6155 KiB  
Article
Artificial Extracellular Vesicles Generated from T Cells Using Different Induction Techniques
by Ekaterina A. Zmievskaya, Sabir A. Mukhametshin, Irina A. Ganeeva, Elvina M. Gilyazova, Elvira T. Siraeva, Marianna P. Kutyreva, Artur A. Khannanov, Youyong Yuan and Emil R. Bulatov
Biomedicines 2024, 12(4), 919; https://doi.org/10.3390/biomedicines12040919 - 20 Apr 2024
Cited by 4 | Viewed by 2259
Abstract
Cell therapy is at the forefront of biomedicine in oncology and regenerative medicine. However, there are still significant challenges to their wider clinical application such as limited efficacy, side effects, and logistical difficulties. One of the potential approaches that could overcome these problems [...] Read more.
Cell therapy is at the forefront of biomedicine in oncology and regenerative medicine. However, there are still significant challenges to their wider clinical application such as limited efficacy, side effects, and logistical difficulties. One of the potential approaches that could overcome these problems is based on extracellular vesicles (EVs) as a cell-free therapy modality. One of the major obstacles in the translation of EVs into practice is their low yield of production, which is insufficient to achieve therapeutic amounts. Here, we evaluated two primary approaches of artificial vesicle induction in primary T cells and the SupT1 cell line—cytochalasin B as a chemical inducer and ultrasonication as a physical inducer. We found that both methods are capable of producing artificial vesicles, but cytochalasin B induction leads to vesicle yield compared to natural secretion, while ultrasonication leads to a three-fold increase in particle yield. Cytochalasin B induces the formation of vesicles full of cytoplasmic compartments without nuclear fraction, while ultrasonication induces the formation of particles rich in membranes and membrane-related components such as CD3 or HLAII proteins. The most effective approach for T-cell induction in terms of the number of vesicles seems to be the combination of anti-CD3/CD28 antibody activation with ultrasonication, which leads to a seven-fold yield increase in particles with a high content of functionally important proteins (CD3, granzyme B, and HLA II). Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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28 pages, 6431 KiB  
Article
Extracellular Vesicles Derived from Osteogenic-Differentiated Human Bone Marrow-Derived Mesenchymal Cells Rescue Osteogenic Ability of Bone Marrow-Derived Mesenchymal Cells Impaired by Hypoxia
by Chenglong Wang, Sabine Stöckl, Girish Pattappa, Daniela Schulz, Korbinian Hofmann, Jovana Ilic, Yvonne Reinders, Richard J. Bauer, Albert Sickmann and Susanne Grässel
Biomedicines 2023, 11(10), 2804; https://doi.org/10.3390/biomedicines11102804 - 16 Oct 2023
Viewed by 1787
Abstract
In orthopedics, musculoskeletal disorders, i.e., non-union of bone fractures or osteoporosis, can have common histories and symptoms related to pathological hypoxic conditions induced by aging, trauma or metabolic disorders. Here, we observed that hypoxic conditions (2% O2) suppressed the osteogenic differentiation [...] Read more.
In orthopedics, musculoskeletal disorders, i.e., non-union of bone fractures or osteoporosis, can have common histories and symptoms related to pathological hypoxic conditions induced by aging, trauma or metabolic disorders. Here, we observed that hypoxic conditions (2% O2) suppressed the osteogenic differentiation of human bone marrow-derived mesenchymal cells (hBMSC) in vitro and simultaneously increased reactive oxygen species (ROS) production. We assumed that cellular origin and cargo of extracellular vesicles (EVs) affect the osteogenic differentiation capacity of hBMSCs cultured under different oxygen pressures. Proteomic analysis revealed that EVs isolated from osteogenic differentiated hBMSC cultured under hypoxia (hypo-osteo EVs) or under normoxia (norm-osteo EVs) contained distinct protein profiles. Extracellular matrix (ECM) components, antioxidants and pro-osteogenic proteins were decreased in hypo-osteo EVs. The proteomic analysis in our previous study revealed that under normoxic culture conditions, pro-osteogenic proteins and ECM components have higher concentrations in norm-osteo EVs than in EVs derived from naïve hBMSCs (norm-naïve EVs). When selected for further analysis, five anti-hypoxic proteins were significantly upregulated (response to hypoxia) in norm-osteo EVs. Three of them are characterized as antioxidant proteins. We performed qRT-PCR to verify the corresponding gene expression levels in the norm-osteo EVs’ and norm-naïve EVs’ parent cells cultured under normoxia. Moreover, we observed that norm-osteo EVs rescued the osteogenic ability of naïve hBMSCs cultured under hypoxia and reduced hypoxia-induced elevation of ROS production in osteogenic differentiated hBMSCs, presumably by inducing expression of anti-hypoxic/ antioxidant and pro-osteogenic genes. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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14 pages, 3348 KiB  
Article
The Influence of Exercise-Associated Small Extracellular Vesicles on Trophoblasts In Vitro
by Shuhiba Mohammad, Jayonta Bhattacharjee, Velislava Tzaneva, Kelly Ann Hutchinson, Madeeha Shaikh, Danilo Fernandes da Silva, Dylan Burger and Kristi B. Adamo
Biomedicines 2023, 11(3), 857; https://doi.org/10.3390/biomedicines11030857 - 11 Mar 2023
Cited by 1 | Viewed by 2359
Abstract
Exercise induces the release of small extracellular vesicles (sEVs) into circulation that are postulated to mediate tissue cross-talk during exercise. We previously reported that pregnant individuals released greater levels of sEVs into circulation after exercise compared to matched non-pregnant controls, but their biological [...] Read more.
Exercise induces the release of small extracellular vesicles (sEVs) into circulation that are postulated to mediate tissue cross-talk during exercise. We previously reported that pregnant individuals released greater levels of sEVs into circulation after exercise compared to matched non-pregnant controls, but their biological functions remain unknown. In this study, sEVs isolated from the plasma of healthy pregnant and non-pregnant participants after a single bout of moderate-intensity exercise were evaluated for their impact on trophoblasts in vitro. Exercise-associated sEVs were found localized within the cytoplasm of BeWo choriocarcinoma cells, used to model trophoblasts in vitro. Exposure to exercise-associated sEVs did not significantly alter BeWo cell proliferation, gene expression of angiogenic growth factors VEGF and PLGF, or the release of the hormone human chorionic gonadotropin. The results from this pilot study support that exercise-associated sEVs could interact with trophoblasts in vitro, and warrant further investigation to reveal their potential role in communicating the effects of exercise to the maternal–fetal interface. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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14 pages, 1082 KiB  
Article
Antimicrobial and Immunomodulatory Potential of Cow Colostrum Extracellular Vesicles (ColosEVs) in an Intestinal In Vitro Model
by Samanta Mecocci, Livia De Paolis, Roberto Zoccola, Floriana Fruscione, Chiara Grazia De Ciucis, Elisabetta Chiaradia, Valentina Moccia, Alessia Tognoloni, Luisa Pascucci, Simona Zoppi, Valentina Zappulli, Giovanni Chillemi, Maria Goria, Katia Cappelli and Elisabetta Razzuoli
Biomedicines 2022, 10(12), 3264; https://doi.org/10.3390/biomedicines10123264 - 15 Dec 2022
Cited by 5 | Viewed by 2615
Abstract
Extracellular Vesicles (EVs) are nano-sized double-lipid-membrane-bound structures, acting mainly as signalling mediators between distant cells and, in particular, modulating the immune response and inflammation of targeted cells. Milk and colostrum contain high amounts of EVs that could be exploited as alternative natural systems [...] Read more.
Extracellular Vesicles (EVs) are nano-sized double-lipid-membrane-bound structures, acting mainly as signalling mediators between distant cells and, in particular, modulating the immune response and inflammation of targeted cells. Milk and colostrum contain high amounts of EVs that could be exploited as alternative natural systems in antimicrobial fighting. The aim of this study is to evaluate cow colostrum-derived EVs (colosEVs) for their antimicrobial, anti-inflammatory and immunomodulating effects in vitro to assess their suitability as natural antimicrobial agents as a strategy to cope with the drug resistance problem. ColosEVs were evaluated on a model of neonatal calf diarrhoea caused by Escherichia coli infection, a livestock disease where antibiotic therapy often has poor results. Colostrum from Piedmontese cows was collected within 24 h of calving and colosEVs were immediately isolated. IPEC-J2 cell line was pre-treated with colosEVs for 48 h and then infected with EPEC/NTEC field strains for 2 h. Bacterial adherence and IPEC-J2 gene expression analysis (RT-qPCR) of CXCL8, DEFB1, DEFB4A, TLR4, TLR5, NFKB1, MYD88, CGAS, RIGI and STING were evaluated. The colosEVs pre-treatment significantly reduced the ability of EPEC/NTEC strains to adhere to cell surfaces (p = 0.006), suggesting a role of ColosEVs in modulating host–pathogen interactions. Moreover, our results showed a significant decrease in TLR5 (p < 0.05), CGAS (p < 0.05) and STING (p < 0.01) gene expression in cells that were pre-treated with ColosEVs and then infected, thus highlighting a potential antimicrobial activity of ColosEVs. This is the first preliminarily study investigating ColosEV immunomodulatory and anti-inflammatory effects on an in vitro model of neonatal calf diarrhoea, showing its potential as a therapeutic and prophylactic tool. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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Review

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37 pages, 2081 KiB  
Review
Effects of Physical Cues on Stem Cell-Derived Extracellular Vesicles toward Neuropathy Applications
by Danyale Berry, Justice Ene, Aakash Nathani, Mandip Singh, Yan Li and Changchun Zeng
Biomedicines 2024, 12(3), 489; https://doi.org/10.3390/biomedicines12030489 - 22 Feb 2024
Cited by 3 | Viewed by 2400
Abstract
The peripheral nervous system undergoes sufficient stress when affected by diabetic conditions, chemotherapeutic drugs, and personal injury. Consequently, peripheral neuropathy arises as the most common complication, leading to debilitating symptoms that significantly alter the quality and way of life. The resulting chronic pain [...] Read more.
The peripheral nervous system undergoes sufficient stress when affected by diabetic conditions, chemotherapeutic drugs, and personal injury. Consequently, peripheral neuropathy arises as the most common complication, leading to debilitating symptoms that significantly alter the quality and way of life. The resulting chronic pain requires a treatment approach that does not simply mask the accompanying symptoms but provides the necessary external environment and neurotrophic factors that will effectively facilitate nerve regeneration. Under normal conditions, the peripheral nervous system self-regenerates very slowly. The rate of progression is further hindered by the development of fibrosis and scar tissue formation, which does not allow sufficient neurite outgrowth to the target site. By incorporating scaffolding supplemented with secretome derived from human mesenchymal stem cells, it is hypothesized that neurotrophic factors and cellular signaling can facilitate the optimal microenvironment for nerve reinnervation. However, conventional methods of secretory vesicle production are low yield, thus requiring improved methods to enhance paracrine secretions. This report highlights the state-of-the-art methods of neuropathy treatment as well as methods to optimize the clinical application of stem cells and derived secretory vesicles for nerve regeneration. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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19 pages, 1275 KiB  
Review
Potential for Therapeutic-Loaded Exosomes to Ameliorate the Pathogenic Effects of α-Synuclein in Parkinson’s Disease
by David J. Rademacher
Biomedicines 2023, 11(4), 1187; https://doi.org/10.3390/biomedicines11041187 - 17 Apr 2023
Cited by 9 | Viewed by 3088
Abstract
Pathogenic forms of α-synuclein (α-syn) are transferred to and from neurons, astrocytes, and microglia, which spread α-syn pathology in the olfactory bulb and the gut and then throughout the Parkinson’s disease (PD) brain and exacerbate neurodegenerative processes. Here, we review attempts to minimize [...] Read more.
Pathogenic forms of α-synuclein (α-syn) are transferred to and from neurons, astrocytes, and microglia, which spread α-syn pathology in the olfactory bulb and the gut and then throughout the Parkinson’s disease (PD) brain and exacerbate neurodegenerative processes. Here, we review attempts to minimize or ameliorate the pathogenic effects of α-syn or deliver therapeutic cargo into the brain. Exosomes (EXs) have several important advantages as carriers of therapeutic agents including an ability to readily cross the blood–brain barrier, the potential for targeted delivery of therapeutic agents, and immune resistance. Diverse cargo can be loaded via various methods, which are reviewed herein, into EXs and delivered into the brain. Genetic modification of EX-producing cells or EXs and chemical modification of EX have emerged as powerful approaches for the targeted delivery of therapeutic agents to treat PD. Thus, EXs hold great promise for the development of next-generation therapeutics for the treatment of PD. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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24 pages, 1822 KiB  
Review
Regenerative Effects of Exosomes-Derived MSCs: An Overview on Spinal Cord Injury Experimental Studies
by Giovanni Schepici, Serena Silvestro and Emanuela Mazzon
Biomedicines 2023, 11(1), 201; https://doi.org/10.3390/biomedicines11010201 - 13 Jan 2023
Cited by 14 | Viewed by 3307
Abstract
Spinal cord injury (SCI) is a devastating condition usually induced by the initial mechanical insult that can lead to permanent motor and sensory deficits. At present, researchers are investigating potential therapeutic strategies to ameliorate the neuro-inflammatory cascade that occurs post-injury. Although the use [...] Read more.
Spinal cord injury (SCI) is a devastating condition usually induced by the initial mechanical insult that can lead to permanent motor and sensory deficits. At present, researchers are investigating potential therapeutic strategies to ameliorate the neuro-inflammatory cascade that occurs post-injury. Although the use of mesenchymal stromal/stem (MSCs) as a potential therapy in application to regenerative medicine promoted anti-inflammatory and neuroprotective effects, several disadvantages limit their use. Therefore, recent studies have reported the effects of exosomes-derived MSCs (MSC-EXOs) as an innovative therapeutic option for SCI patients. It is noteworthy that MSC-EXOs can maintain the integrity of the blood-spinal cord barrier (BSCB), promoting angiogenic, proliferative, and anti-oxidant effects, as well as immunomodulatory, anti-inflammatory, and antiapoptotic properties. Therefore, in this study, we summarized the preclinical studies reported in the literature that have shown the effects of MSC-EXOs as a new molecular target to counteract the devastating effects of SCI. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents)
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