Extracellular vesicles as tools and targets in therapy for diseases

Abstract

Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.

Fig. 1

Visual depiction of the variety and sources of EVs. EVs encapsulate an array of bioactive entities, including proteins, nucleic acids, and lipids, which not only form structural components but also bear specific cellular signatures. Cells from diverse tissue origins employ EVs as vehicles for intercellular communication, releasing them into adjacent body fluids. In humans, a notable proportion of EVs emanate from stem cells. Beyond humans, various organisms, from plants to bacteria, also actively produce and release EVs into their environment

Fig. 2

EVs are enriched in body fluids. This figure highlights the ubiquity of EVs across various body fluids. Liquid biopsy, which enables the non-invasive capture and analysis of EVs from fluids, including saliva, milk, blood, and urine, stands at the forefront of advancements in cancer diagnosis and prognosis prediction. The clinical relevance of EVs extends to monitoring therapeutic responses and forecasting disease outcomes. Their widespread presence in biofluids positions EVs as invaluable tools for refining patient management in oncology

Fig. 3

Comprehensive role of extracellular vesicles in cancer progression. This diagram delineates the intricate interplay of EVs in various cancer dynamics. Through the transportation of specific EV-associated molecules, they govern a range of tumorigenic processes, including: 1. Invasion and Metastasis: The cargo within EVs can promote the breakdown of extracellular matrix, paving the way for cancer cells to invade surrounding tissues. EVs can impart migratory capabilities to tumor cells, aiding their movement and potential metastatic spread. 2. Angiogenesis: By transmitting pro-angiogenic factors, EVs form new blood vessels, thereby supporting tumor growth and expansion. 3. Immunomodulation: EVs can modulate the TME by influencing the behavior of immune cells, potentially facilitating tumor evasion from immune surveillance

Fig. 4

The multifunctional landscape of tumor-derived extracellular vesicles in tumorigenesis. This figure provides a detailed insight into the multifunctional activities of EVs emanating from cancer cells and their role in advancing tumorigenesis. Tumor-derived EVs encapsulate diverse bioactive molecules, including miRNAs, specific cytokines, and oncogenes. These molecular constituents determine the functional role of the EVs. EVs transport growth-promoting miRNAs and oncogenes to neighboring cancer cells, fueling their uncontrolled division and expansion.The EVs instigate a transformative process in epithelial cells by delivering specific miRNAs and proteins, endowing them with mesenchymal traits that enhance mobility and invasiveness.EVs convey pro-angiogenic factors to endothelial cells, stimulating the sprouting of new blood vessels, which nourish and support the expanding tumor mass. By presenting specific immunosuppressive cytokines and miRNAs to immune cells, such as macrophages, the EVs create an environment conducive to tumor evasion from immune surveillance. The EVs actively engage with various stromal cells, notably cancer-associated fibroblasts (CAFs) and macrophages. This cellular crosstalk, mediated by EVs, reshapes the tumor milieu, promoting a supportive scaffold and immune-tolerant backdrop for cancer progression

Fig. 5

Extracellular vesicles for anti-tumor therapies. Extracellular vesicles (EVs) are gaining recognition for their potential therapeutic applications, particularly in oncology. Due to their inherent circulation stability and proficiency in mediating horizontal cargo transfer, EVs can be harnessed as carriers, loaded with various therapeutic agents ranging from chemotherapeutics to tumor-specific RNA interference molecules. Their natural ability to target specific cell populations makes them an ideal medium for precise drug delivery.EVs can be equipped with specific ligands to target malignant cells in diverse disease states, ensuring that therapeutic agents reach their intended sites with minimal off-target effects. By engineering EVs to display certain proteins, such as PD1 or tumor-specific antigen peptides, they can be transformed into tools for modulating the immune system. This strategy can amplify the body’s natural defense against cancers, potentially mitigating tumor growth or even initiating tumor regression. Researchers have devised innovative ways to repurpose EVs as vaccine platforms. By manipulating their content or surface properties, EVs can serve as promising candidates for next-generation vaccines, particularly for malignancies

Fig. 6

Pathological implications of extracellular vesicles in disease progression. a Neurological disorders. Cells such as microglia, astrocytes, and endothelial cells release EVs that transport neuropathological proteins like Aβ, Tau, and α-synuclein alongside specific miRNAs. These EVs can spread these harmful components across the brain, potentially accelerating neurodegenerative processes. Moreover, certain neurotoxic EVs can traverse the blood-brain barrier, disseminating their deleterious cargo to other neurons and amplifying neural dysfunction. b Cardiovascular Complications: EVs emanating from inflamed or damaged endothelial cells, as well as those from inflammatory cells, often display cell adhesion molecules and procoagulant markers. When the endothelium is compromised, these EVs adhere to the vascular wall, potentially instigating cardiomyocyte hypertrophy. Notably, patients suffering from acute coronary syndrome (ACS) demonstrate elevated concentrations of these circulating procoagulant endothelial microparticles. Over time, these contribute to atherosclerotic plaque formation, eventually risking blockage of coronary arteries. c Diabetes: In the diabetic milieu, EVs released within the pancreas carry detrimental miRNAs and pro-inflammatory cytokines. These EVs can instigate the apoptosis of insulin-producing β cells by activating specific immune cells, namely B and T cells. Furthermore, in type 2 diabetes (T2D), these EVs potentially reduce the efficacy of glucose transporters, exacerbating the disease. d Viral Infections & Oncogenesis: Cells infected by specific pathogens generate EVs that encapsulate viral components, facilitating their transfer to healthy cells. Some pathogens possess the capability to modify the content of EVs, leading to scenarios like T-cell apoptosis, potentially promoting oncogenesis. e Autoimmune Diseases: Physiological stress can spur the release of EVs enriched with autoantigens, inflammatory cytokines, and specific genetic elements (e.g., miRNA, DNA). These EVs can bind with antibodies and platelets to create immune complexes (ICs). These ICs then prime antigen-presenting cells, culminating in an intensified autoimmune reaction. This cascade can lead to heightened cellular destruction, as seen with the release of EVs from damaged synovial fibroblasts in RA. f Renal Disease & Organ Interplay: EVs circulating systemically facilitate communication between organs, and their dysregulated activities have been implicated in amplifying kidney damage and inflammation. These vesicles can potentially exacerbate renal ailments by fostering detrimental cellular interactions and inflammatory responses