Extracellular vesicles (EVs) are lipid-bound particles released by tumor cells and widely explored in cancer development, progression, and treatment response, being considered as valuable components to be explored as biomarkers or cellular targets to modulate the effect of therapies. The mechanisms underlying the production and profile of EVs during radiotherapy (RT) require addressing radiobiological aspects to determine cellular responses to specific radiation doses and fractionation. In this review, we explore the role of EVs in the 7 Rs of radiobiology, known as the molecular basis of a biological tissue response to radiation, supporting EVs as a shared player in all the seven processes. We also highlight the relevance of EVs in the context of liquid biopsy and resistance to immunotherapy, aiming to establish the connection and utility of EVs as tools in contemporary and precision radiotherapy.

Multiple myeloma (MM) is a blood cancer characterized by the uncontrolled growth of plasma cells in the bone marrow. These malignant plasma cells can proliferate locally and spread to other tissues and organs. The M-protein they produce can lead to various clinical symptoms, including anemia, hypercalcemia, bone pain, bone destruction, and kidney dysfunction. Despite significant advancements in treatment over the past two decades that have improved survival and outcomes for many patients, drug resistance remains a significant therapeutic challenge. This resistance is largely driven by the complex interactions between MM cells and the bone marrow microenvironment (BMME), making long-term disease control difficult. To improve treatment outcomes, it is essential to understand how the BMME supports MM cell growth and survival, as well as how these cells evade therapies. Investigating these processes will help identify key mechanisms behind drug resistance, offering a pathway to develop targeted therapies that can overcome this challenge. This review will explore the intricate relationship between MM cells and the BMME, focusing on how both cellular and non-cellular components of the microenvironment contribute to resistance mechanisms and prompt disease progression. These insights aim to inform future therapeutic strategies to enhance treatment options for MM patients.

Wound healing presents a significant challenge in healthcare, imposing substantial physiological and economic burdens. While traditional treatments and stem cell therapies have shown benefits, milk-derived exosomes (MDEs) offer distinct advantages as a cell-free therapeutic approach. MDEs, isolated from mammalian milk, are characterized by their biocompatibility, ease of acquisition, and high yield, making them a promising tool for enhancing wound repair. This review provides a comprehensive analysis of the composition, sources, and extraction methods of MDEs, with a focus on their therapeutic role in both acute and diabetic chronic wounds. MDEs facilitate wound healing through the delivery of bioactive molecules, modulating key processes such as inflammation, angiogenesis, and collagen synthesis. Their ability to regulate complex wound-healing pathways underscores their potential for widespread clinical application. This review highlights the importance of MDEs in advancing wound management and proposes strategies to optimize their use in regenerative medicine.

miR-135b, a microRNA, is consistently up-regulated in various cancer tissues and cells, promoting cancer progression. By inhibiting one or more target genes, miR-135b regulates phenotypes such as cancer growth, apoptosis, migration, invasion, drug resistance, and angiogenesis, establishing it as a critical driver of cancer progression. Additionally, miR-135b is regulated by various oncogenes and therapeutic drugs, highlighting its complexity and therapeutic potential. Significant progress has been made in understanding miR-135b's impact on cancer cell behavior, establishing it as a promising biomarker for cancer diagnosis and prognosis, as well as a potential target for future cancer therapies. However, despite the extensive research on this topic, there has been no comprehensive review summarizing its role and mechanisms across different cancer types. This review aims to provide a detailed overview of the biological characteristics of miR-135b, its regulatory targets, upstream signaling pathways, and its therapeutic potential, including its influence on cancer chemoresistance. The review also addresses key controversies surrounding miR-135b in cancer research, aiming to deepen the understanding of its role, promote the transformation of its clinical application, and provide a theoretical foundation for developing more effective cancer treatment strategies.

The premetastatic niche (PMN) represents a metastasis-facilitative microenvironment established prior to tumor dissemination, initiated by vascular leakage and endothelial cell (EC) functional remodeling. ECs play pivotal roles as bridges in different stages of the metastatic cascade. As critical stromal components within the PMN, ECs not only drive angiogenesis but also actively orchestrate immune suppression, extracellular matrix (ECM) remodeling, and the inflammatory signaling characteristic of PMN formation, with multiple specific signaling pathways such as VEGF/Notch playing a crucial role. With the evolving understanding of the role of ECs in controlling tumor metastasis, therapeutic strategies targeting ECs within the PMN, such as antiangiogenic therapy (AAT), targeting of endothelial glycocalyx (GCX), inhibition of tumor-derived exosome (TDE) and angiocrine signaling, are becoming research hotspots. This review systematically delineates the cellular and molecular composition of PMNs, dynamically dissects their spatiotemporal evolution, and highlights organ-specific mechanisms of EC-driven PMN establishment. Furthermore, we summarize emerging EC-targeted therapeutic strategies, providing innovative insights for inhibiting tumor metastasis.

Unlike traditional small-molecule agents, biopharmaceuticals, like synthetic RNAs, enzymes, and monoclonal antibodies, are highly vulnerable to environmental conditions. Preservation of their functional integrity necessitates advanced delivery methods. Being biocompatible, extracellular vesicles (EVs) gained attention as a promising system for delivering biopharmaceuticals, addressing challenges related to the stability and efficacy of sensitive therapeutic molecules. Indeed, EVs can cross biological barriers like the blood-brain barrier, delivering therapeutic cargo to tissues that are traditionally difficult to reach. Recent innovations in surface modification technologies, including ligand and antibody attachment, have further enhanced EVs' targeting capabilities, making them particularly effective in personalized medicine. Here, we review the versatile suitability of EVs for being next-generation delivery vehicles of biopharmaceuticals, including current standings, practical challenges, and possible future directions of the technology.

Exosomes represent extracellular vesicles that mediate intercellular interactions and have been extensively studied for their therapeutic potential. Purified exosomes product (PEP) from human plasma is reported to aid in tissue repair but has never been evaluated as a potential therapy for spinal cord injury (SCI).

We aim to investigate the effects of PEP on axon myelination, reduction in cavity size, and functional improvements in rats following SCI.

Following T9-T10 laminectomy and contusion to the spinal cord, female rats received either intrathecal (IT) PEP, IT ringer-lactate solution (RL), intravenous (IV) PEP, or IV RL one day post injury. Rats underwent behavioral assessments each week for 10 weeks following SCI. After 10 weeks, histological evaluations were performed to quantity axon myelination and cavity size.

The IT PEP group had significantly (P ≤ 0.05) more myelinated axons 1000 μm rostral to the injury, at the epicenter, and 1000 μm caudal of the injury (34.3 ± 3.1, 27.7 ± 2.1, and 32.0 ± 1.7, respectively) compared to the IT RL group (27.3 ± 2.5, 17.3 ± 2.5, and 23.3 ± 2.5, respectively). In addition, IT PEP rats had significantly reduced cavity size at the injury epicenter compared to controls (28.31%±1.74% vs. 34.39%±3.78%, respectively). Lastly, functional improvements were observed and sustained beginning at the 31 days following injury. The IV PEP group did not show sustained functional improvement compared to the IV RL rats.

Our results suggest that IT PEP injection may yield beneficial effects following SCI. However, further studies are warranted to investigate the role of PEP following SCI and to optimize its potential for clinical translation.

Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8+ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS-miRNA-exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds-such as curcumin, resveratrol, and ginsenosides-which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer.

Circular RNAs (circRNAs) are a type of non coding RNA that possess unique single stranded circular structures formed through reverse splicing mechanisms. Due to the lack of a free end that is typically susceptible to degradation by nucleases, circular RNAs exhibit resistance to ribonuclease R, making them highly stable in eukaryotic cells. The complex relationship between circRNA dysregulation and various pathophysiological conditions, especially cancer. Tumor microenvironment (TME) is a collective term for various components surrounding tumors and is an important factor affecting tumor development. Simultaneous infiltration of TME by different types of immune cells; These immune cells interact with the TME, collectively forming the so-called "tumor immune microenvironment". The complex interactions between tumor cells and TME profoundly affect the behavior of malignant tumors, and circRNAs derived from tumor cells and TME cell components have become important mediators of immune response and evasion within the TME. CircRNAs can directly or indirectly regulate immune cells, thereby modulating anti-tumor immunity. This review highlights how circRNAs, especially those encapsulated in extracellular vesicles like exosomes, influence the differentiation, chemotaxis, and anti-tumor immune functions of immune cells within the TME. Metabolic reprogramming plays an important role in this process. The process of circRNAs regulating tumor immunity is affected by multiple factors, such as hypoxia and viral infection. This review emphasizes the roles of the interaction between circRNAs and the TME in tumor immune regulation and prospects the guiding significance of circRNAs in tumor immune checkpoint therapy.

Multiple myeloma (MM), characterised by the clonal proliferation of plasma cells in the bone marrow, is the second most common haematological malignancy worldwide. Although there is now an impressive artillery of therapeutics to tackle this condition, resistance remains a prevalent issue. The bone marrow microenvironment performs a crucial role in supporting MM pathogenesis and promoting the development of therapeutic resistance. Extracellular vesicles (EVs), small vesicles that carry bioactive molecules, are a key component of cell-to-cell communication within the bone marrow microenvironment. In this review, we summarise the contribution of EVs to disease progression and anticancer treatment resistance and discuss the potential therapeutic applications of EVs in MM.

Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.

Extracellular vesicles (EVs), tiny packages of information released by cells, are well established as being involved in unwanted cell-to-cell communication in cancer. EVs from cancer cells have been associated with the spread of drug resistance, immune suppression, and metastasis. Additional to cancer cells, the tumour microenvironment (TME) involves many cell types -including immune cells, fibroblasts, and endothelial cells, each of which has a potential role in how tumours grow, spread, and respond (or otherwise) to therapy. This review collates and distils research developments regarding the role of EVs in multi-way communication between cells in the TME. Further research including tailored clinical studies are now warranted to determine how best to prevent this extensive adverse communication occurring and/or how best to exploit it for biomarker discovery and as a therapeutic approach, in the interest of patients and also for economic benefit.

These findings provide a critical first step in characterizing the capacity of OS-derived exosomes to reprogram primary LFs toward a tumor-promoting inflammatory phenotype in vitro, offering novel molecular targets for the modulation of fibroblasts in the lung microenvironment as potential therapeutic strategies to prevent OS metastasis.

Fructose-1,6-bisphosphatase 1 (FBP1) is the enzyme that limits the process of gluconeogenesis as it facilitates the hydrolysis of fructose-1,6-bisphosphate(F-1,6-BP) to produce fructose-6-phosphate(F6P) and inorganic phosphate. Gluconeogenesis is the production of glucose from small carbohydrate substrates. The gluconeogenic process is typically suppressed in cancer because it inhibits glycolysis. Apart from its involvement in cellular glucose metabolism, FBP1 also plays a role in gene transcription, mRNA translation and stability regulation, and the immune microenvironment of tumors. Because of its multifaceted functions, the mechanisms by which FBP1 is involved in tumor development are complex. Moreover, FBP1 deficiency is associated with radiation and chemotherapy resistance and poor prognosis in cancer patients. Restoration of FBP1 expression in cancer cells is expected to hold promise for cancer therapy. However, up to now few reviews have systematically summarized the important functional mechanisms of FBP1 in tumorigenesis and the small molecule compounds that restore FBP1 expression. Therefore, this article addresses the question "How does FBP1 contribute to cancer progression, and can targeting FBP1 be a potential therapeutic approach?" by summarizing the effects of FBP1 on cancer development and progression as well as its mediated drug resistance and the future clinical applications of potential small molecule modulators targeting FBP1.

The growth of blood vessels from the existing vasculature has a significant impact on the course of multiple myeloma (MM). The ANGPT2 (angiopoietin-2) protein is encoded by the ANGPT2 gene and plays an important role in angiogenesis. The expression of proangiogenic proteins is influenced not only by microenvironmental factors but also by genetic changes. We analyzed two variants/polymorphisms of the ANGPT2 gene, rs1868554 (T>A) and rs7825407 (G>C). Both are located in the intron sequence and can affect the final mRNA sequence by modifying splicing.

Therefore, we assessed the impact of selected variants on ANGPT2 gene expression at the mRNA and protein levels. Additionally, we evaluated the associations of the analyzed genetic changes with the clinical and laboratory parameters of the disease and the response to bortezomib/thalidomide-based therapies. We hypothesize that variants and expression of the ANGPT2 gene may be associated with a greater risk of MM development and may also affect the response to treatment in MM patients.

Genomic DNA extracted from 103 newly diagnosed MM patients and 120 healthy blood donors was used to analyze ANGPT2 variants (via automated DNA sequencing). RNA was subjected to real-time PCR to determine ANGPT2 expression at the mRNA level. The concentration of angiopoietin-2 (in MM sera) was determined by ELISA.

The results of our study showed that individuals with the AA genotype of rs1868554 and the CC genotype of rs7825407 had a greater risk of developing MM (OR=6.12, p=0.02 and OR=6.01, p=0.02, respectively). The ANGPT2 gene variants did not affect ANGPT2 expression at the mRNA level. However, ANGPT2 expression was positively correlated with CRP (Spearman's rho 0.26, p<0.05) and negatively correlated with LDH (Spearman's rho -0.25, p<0.05) in MM patients.

Our results showed that ANGPT2 expression at the mRNA level correlates with CRP, a negative prognostic factor in MM. The ANGPT2 protein is a proangiogenic factor, and its concentration is significantly greater in MM patients than in healthy individuals, which was also confirmed in our research. Therefore, this protein with VEGF and HB-EGF, should be considered in the future as a markers of angiogenesis in MM.

MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs found in eukaryotes with post-transcriptional regulatory functions. A variety of miRNAs is differentially expressed in cancer tissues and thus can be used as biomarkers. microRNA-135b-5p (miR-135b) has been shown to be involved in the pathological processes of a variety of neoplastic and non-neoplastic diseases. Under different conditions, miR-135b has different tumor suppressive and carcinogenic effects. miR-135b regulates the development of cancer, including metabolism, proliferation, apoptosis, invasion, fibrosis, angiogenesis, immunomodulation, and drug resistance. miR-135b can be used as a new biomarker for tumor diagnosis and prognosis, which has the potential for clinical guidance. This article reviews the relevant research on miR-135B in the field of tumors, including the biogenesis background of miR-135b, the expression of miR-135b in tumors, and the related targets and signaling pathways of miR-135b mediating tumor progression in order to sort out and explore the clinical transformation value of miR-135b.

Extracellular vesicles (EVs), nanoscale vesicles secreted by cells, have attracted considerable attention in recent years due to their role in tumor immunomodulation. These vesicles facilitate intercellular communication by transporting proteins, nucleic acids, and other biologically active substances, and they exhibit a dual role in tumor development and immune evasion mechanisms. Specifically, EVs can assist tumor cells in evading immune surveillance and attack by impairing immune cell function or modulating immunosuppressive pathways, thereby promoting tumor progression and metastasis. Conversely, they can also transport and release immunomodulatory factors that stimulate the activation and regulation of the immune system, enhancing the body's capacity to combat malignant diseases. This dual functionality of EVs presents promising avenues and targets for tumor immunotherapy. By examining the biological characteristics of EVs and their influence on tumor immunity, novel therapeutic strategies can be developed to improve the efficacy and relevance of cancer treatment. This review delineates the complex role of EVs in tumor immunomodulation and explores their potential implications for cancer therapeutic approaches, aiming to establish a theoretical foundation and provide practical insights for the advancement of future EVs-based cancer immunotherapy strategies.

The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.

In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.

Angiostrongylus cantonensis is a significant foodborne zoonotic parasite that causes severe neuropathological damage and symptoms in humans. Excretory-secretory products (ESPs) play a pivotal role in elucidating host-parasite interactions and can aid in penetrating host defensive barriers in helminths. Recently, secreted microRNAs have become important research targets for parasite-host communication. In this study, we determined the expression and function of novel microRNAs from A. cantonensis L5 ESPs and evaluated the effect of target microRNAs on the molecular mechanisms of mouse astrocytes.

Here, we employed next-generation sequencing (NGS) to establish the secreted microRNAs dataset. Next, we evaluated the effects of AcESPs-microRNAs in A. cantonensis ESPs treated astrocytes.

First, we established the secreted microRNA dataset, and then comprehensively verified the characteristics. Novel microRNAs were initially detected, and their expression was found. Moreover, the prediction results showed that these secreted microRNAs may regulate Wnt and mTOR signaling. Next, the data showed that the AcNOVEL55 microRNA reduced cell apoptosis generation via regulating the RhoA-Rock signaling pathway in A. cantonensis L5 ESPs treated mouse astrocytes. Moreover, we also demonstrated that the AcNOVEL31 microRNA can affect the inflammation activation via regulating the presenilin-1/GSK3B/β-catenin/NF-κB pathway. Finally, the concentrations of secreted IL-6 and IL-12 proteins were downregulated by AcNOVEL31 microRNA by influencing presenilin-1 expression.

This is the first study to verify the molecular functions of novel microRNAs secreted by A. cantonensis. The discovery of the microRNA mechanisms by which cross-species parasitic nematodes influence hosts has advanced research on host-parasitic nematode interactions.

Exosomes are membrane-bound extracellular vesicles that play a role in exchanging biological products across membranes and serve as intermediaries in intercellular communication to maintain normal homeostasis. Numerous molecules, including lipids, proteins, and nucleic acids are enclosed in exosomes. Exosomes are constantly released into the extracellular environment and exhibit distinct characteristics based on the secreted cells that produce them. Exosome-mediated cell-to-cell communication has reportedly been shown to affect multiple cancer hallmarks, such as immune response modulation, pre-metastatic niche formation, angiogenesis, stromal cell reprogramming, extracellular matrix architecture remodeling, or even drug resistance, and eventually the development and metastasis of cancer cells. Exosomes can be used as therapeutic targets and possible diagnostic biomarkers by selectively loading oncogenic molecules into them. We highlight the important roles that exosomes play in cancer development in this review, which may lead to the development of fresh approaches for future clinical uses.

Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication in cancer. These membranous structures, secreted by normal and cancerous cells, carry a cargo of bioactive molecules including microRNAs (miRNAs) that modulate various cellular processes. miRNAs are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation and have been implicated in cancer initiation, progression, and metastasis. In cancer, tumor-derived EVs transport specific miRNAs to recipient cells, modulating tumorigenesis, growth, angiogenesis, and metastasis. Dysregulation of miRNA expression profiles within EVs contributes to the acquisition of cancer hallmarks that include increased proliferation, survival, and migration. EV miRNAs influence the tumor microenvironment, promoting immune evasion, remodeling the extracellular matrix, and establishing pre-metastatic niches. Understanding the complex interplay between EVs, miRNAs, and cancer holds significant promise for developing novel diagnostic and therapeutic strategies. This chapter provides insights into the role of EV-mediated miRNA signaling in cancer pathogenesis, highlighting its potential as a biomarker for cancer detection, prognosis, and treatment response assessment.

Exosomes are small extracellular vesicles of endocytic origin released by various cell types. They consist of lipid bilayers containing macromolecules such as lipids, proteins, microRNAs, growth factors, cytokines, and carbohydrates. Exosomes play a critical role in the diagnosis and treatment of various diseases. For instance, exosome contents have been utilized as biomarkers in body fluids (urine, saliva, serum) to identify cancers, autoimmune diseases, and inflammatory conditions such as sepsis. Due to their small size and ability to reach tumor microenvironments, exosomes are also used as carriers for chemotherapeutic drugs in drug delivery systems. Furthermore, evidence indicates that malignant cells release exosomes into the tumor microenvironment, influencing immune cells in a paracrine manner. Additionally, immune cell-derived exosomes, such as those from Natural Killer (NK) cells or cytotoxic T lymphocytes (CTLs), show potential as therapeutic agents in treating malignancies like leukemia. This review discusses the diagnostic role of exosomes in various hematological malignancies and explores the therapeutic potential of immune cell-derived exosomes in these diseases.

Multiple myeloma is a plasma cell malignancy characterized by an abnormal increase in monoclonal immunoglobulins. Despite significant advances in treatment, some patients progress to more aggressive forms of multiple myeloma, including extramedullary disease or plasma cell leukemia. Although the exact molecular mechanisms are not known, several studies have confirmed the involvement of small extracellular vesicle-enriched microRNAs in multiple myeloma progression. Therefore, we performed expression profiling of these molecules in bone marrow plasma of multiple myeloma, extramedullary disease, and plasma cell leukemia patients using small RNA sequencing to identify novel molecules involved in disease pathogenesis. In total, 42 microRNAs were significantly dysregulated among analyzed subgroups. Independent validation by RT-qPCR confirmed elevated levels of miR-140-3p, miR-584-5p, miR-191-5p, and miR-143-3p in multiple myeloma patients compared to extramedullary disease and plasma cell leukemia patients. Subsequent statistical analysis revealed significant correlations between patient clinical characteristics or flow cytometry parameters and microRNA expression. These results indicate that dysregulation of microRNAs could contribute to multiple myeloma progression.

The exosomes from adipose-derived mesenchymal stem cells (AMSCs) had therapeutic effects. However, whether the exosomes derived from hypoxia-treated AMSCs could improve renal functions in unilateral ureteral obstruction (UUO) mice remains unclear.

The exosomes were characterized using a transmission electron microscope and Western blot. Its size distribution was determined using the Zetasizer Nano ZS analysis system. The differentiation ability was assessed by alkaline phosphatase and oil red staining. Consequently, the function of exosomes in inhibiting inflammatory factors was evaluated using an enzyme-linked immunosorbent assay, and apoptosis inhibition was evaluated by Western blot. Finally, the function of exosomes to ameliorate kidney fibrosis was evaluated using quantitative reverse transcription polymerase chain reaction, Western blot, hematoxylin-eosin staining, and Masson staining.

The cultured AMSCs could differentiate into osteoblast and adipocyte. Meanwhile, the cultured AMSCs could effectively secrete the exosomes, which were characterized by around 110 nm diameter and surface marker expression. Exosomes derived from hypoxia-treated AMSCs improved renal functions in UUO mice. The mechanism exploration revealed that exosomes could decrease the TNF-α and IL-6 and inhibit cell apoptosis. Finally, the fibrosis-associated protein was reversed, and the renal dysfunctions were ameliorated in UUO mice.

The exosomes derived from the hypoxia-treated AMSCs have a better effect than those from normal AMSCs in ameliorating renal dysfunctions in UUO mice.

Extracellular vesicles (EVs) have emerged as pivotal regulators for extensive intercellular crosstalk owing to capsuled diverse bioactive substances such as proteins, nucleic acids, and lipids. Recent studies have shown that tumor-derived EVs significantly influence the bone marrow microenvironment, contributing to the progression of multiple myeloma (MM). This highlights the robust potential of EVs as a promising avenue for developing more effective and precise diagnostic and therapeutic strategies for MM. In this review, we briefly discuss the multifaceted roles of EVs in MM progression, as well as the diagnostic and therapeutic value in MM management. Specifically, we focus on the latest research progress regarding the therapeutic potential of EVs for MM, particularly tumor cell-derived EVs, as we elaborate on three main aspects: (i) EVs as therapeutic targets, including the targeted inhibition of EV biogenesis and uptake, and the possibility of eliminating tumor-derived EVs; (ii) EVs as delivery nanovectors, where we discuss the latest anti-MM candidates and potential ways to optimize therapeutic efficiency; and (iii) engineered EVs as antitumor vaccines, focusing on the use of tumor cell-derived EVs in immunotherapy. Finally, we address the prospects and challenges of harnessing the therapeutic potential of EVs in clinical transformation.

Hematological malignancies originate from the hematopoietic system, including lymphoma, multiple myeloma, leukaemia, etc. They are highly malignant with a high incidence, a poor prognosis and a high mortality. Although the novel therapeutic strategies have partly improved the clinical efficacy of hematological malignancies, patients still face up with drug resistance, refractory disease and disease relapse. Many studies have shown that exosomes play an important role in hematological malignancies. Exosomes are nanoscale vesicles secreted by cells with a size ranging from 40 to 160 nm. They contain various intracellular components such as membrane proteins, lipids, and nucleic acids. These nanoscale vesicles transmit information between cells with the cargos. Thus, they participate in a variety of pathological processes such as angiogenesis, proliferation, metastasis, immunomodulation and drug resistance, which results in important role in the pathogenesis and progression of hematological malignancies. Furthermore, exosomes and the components carried in them can be used as potential biomarkers for the diagnosis, therapeutic sensitivity and prognosis in hematological malignancies. In the therapy of hematologic malignancies, certain exosome are potential to be used as therapeutic targets, meanwhile, exosomes are suitable drug carriers with lipid bilayer membrane and the nanostructure. Moreover, the tumor-derived exosomes of patients with hematologic malignancies can be developed into anti-tumor vaccines. The research and application of exosomes in hematological malignancies are summarized and discussed in this review.

Papillary thyroid carcinoma (PTC) is one of the most common subtypes of thyroid carcinoma. Exosomal miR-181a plays an important role in the development of PTC. This study examined the regulatory mechanism of miR-181a under conditions of hypoxia and its impact on angiogenesis.

A ribonucleoprotein immunoprecipitation (RIP) experiment was conducted to verify the interaction between HOTAIR and RELA. The relationship between RELA and the miR-181a promoter was detected by ChIP-qPCR. Short hairpin (sh) RNA was designed to knock down HOTAIR in TPC cells. The underlying mechanism of miR-181a was verified by use of dual-luciferase assays and rescue experiments. The regulatory effect of GATA6 on angiogenesis was studied using CCK8, EdU, Transwell, and western blot assays.

A RIP assay showed that HOTAIR could bind to RELA under hypoxic conditions. ChIP-qPCR and dual luciferase assays showed RELA could interact with the miR181a promoter and upregulate miR-181a. Knockdown of HOTAIR downregulated miR-181a in TPC-1 cells, and the downregulation could be rescued by RELA overexpression. MiR-181a downregulated GATA6 in HUVEC cells. Overexpression of GATA6 inhibited HUVEC proliferation, migration, tube formation, and EGFR expression. Exosomal miR-181a promoted angiogenesis by downregulating GATA6 expression.

HOTAIR activated RELA to upregulate miR-181a during hypoxia. Exosomal miR-181a promotes tumor angiogenesis by downregulating GATA6.

Tissue engineering for penile corpora cavernosa defects requires microvascular system reconstruction.GelMA hydrogels show promise for tissue regeneration. However, using stem cells faces challenges such as immune rejection, limited proliferation and differentiation, and biosafety concerns. Therefore, acellular tissue regeneration may avoid these issues. Exosomes are used from muscle-derived stem cells (MDSCs) to modify 3D-printed hydrogel scaffolds for acellular tissue regeneration. Hypoxia-preconditioned MDSC-derived exosomes are obtained to enhance the therapeutic effect. In contrast to normoxic exosomes (N-Exos), hypoxic exosomes (H-Exos) are found to markedly enhance the proliferation, migration, and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). High-throughput sequencing analysis of miRNAs isolated from both N-Exos and H-Exos revealed a significant upregulation of miR-21-5p in H-Exos following hypoxic preconditioning. Further validation demonstrated that the miR-21-5p/PDCD4 pathway promoted the proliferation of HUVECs. Epigallocatechin gallate (EGCG) is introduced to improve the mechanical properties and biocompatibility of GelMA hydrogels. EGCG-GelMA scaffolds loaded with different types of Exos are transplanted to repair rabbit penile corpora cavernosa defects, observed the blood flow and repair status of the defect site through color Doppler ultrasound and magnetic resonance imaging, and ultimately restored the rabbit penile erection function and successfully bred offspring. Thus, acellular hydrogel scaffolds offer an effective treatment for penile corpora cavernosa defects.

Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.

Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field.

Exosomes are extracellular vesicles well known for facilitating cell-to-cell communication by distributing essential macromolecules like proteins, DNA, mRNA, lipids, and miRNA. These vesicles are abundant in fluids distributed throughout the body, including urine, blood, saliva, and even bile. They are important diagnostic tools for breast, lung, gastrointestinal cancers, etc. However, their application as cancer biomarkers has not yet been implemented in most parts of the world. In this review, we discuss how OMICs profiling of exosomes can be practiced by substituting traditional imaging or biopsy methods for cancer detection. Previous methods like extensive imaging and biopsy used for screening were expensive, mostly invasive, and could not easily provide early detection for various types of cancer. Exosomal biomarkers can be utilized for routine screening by simply collecting body fluids from the individual. We anticipate that the use of exosomes will be brought to light by the success of clinical trials investigating their potential to enhance cancer detection and treatment in the upcoming years.

Glioblastoma poses significant challenges in oncology, with bevacizumab showing promise as an antiangiogenic treatment but with limited efficacy. microRNAs (miRNAs) 10b and 21 have emerged as potential biomarkers for bevacizumab response in glioblastoma patients. This study delves into the expression dynamics of miR-21 and miR-10b in response to hypoxia and explores their circulation mechanisms. In vitro experiments exposed glioma cells (A172, U87MG, U251) and human umbilical vein endothelial cells (HUVEC) to hypoxic conditions (1% oxygen) for 24 h, revealing heightened levels of miR-10b and miR-21 in glioblastoma cells. Manipulating miR-10b expression in U87MG, demonstrating a significant decrease in VEGF alpha (VEGFA) following miR-10b overexpression under hypoxic conditions. Size exclusion chromatography illustrated a notable shift towards miR-21 and miR-10b exosomal packaging during hypoxia. A proposed model suggests that effective bevacizumab treatment reduces VEGFA levels, heightening hypoxia and subsequently upregulating miR-21 and miR-10b expression. These miRNAs, released via exosomes, might impact various cellular processes, with miR-10b notably contributing to VEGFA level reduction. However, post-treatment increases in miR-10b and miR-21 could potentially restore cells to normoxic conditions through the downregulation of VEGF. This study highlights the intricate feedback loop involving miR-10b, miR-21, and VEGFA in glioblastoma treatment, underscoring the necessity for personalized therapeutic strategies. Further research should explore clinical implications for personalized glioma treatments.

Multiple myeloma (MM) is the most prevalent malignant monoclonal disease of plasma cells. There is mounting evidence that interactions with the bone marrow (BM) niche are essential for the differentiation, proliferation, survival, migration, and treatment resistance of myeloma cells. For this reason, gaining a deeper comprehension of how BM microenvironment compartments interact with myeloma cells may inspire new therapeutic ideas that enhance patient outcomes. This review will concentrate on the most recent findings regarding the mechanisms of interaction between microenvironment and MM and highlight research on treatment targeting the BM niche.

Solid tumors frequently experience hypoxia or low O2 levels. In these conditions, hypoxia-inducible factor 1 alpha (HIF-1α) is activated and acts as a transcription factor that regulates cancer cell adaptation to O2 and nutrient deprivation. HIF-1α controls gene expression associated with various signaling pathways that promote cancer cell proliferation and survival. MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs that play a role in various biological processes essential for cancer progression. This review presents an overview of how hypoxia regulates the expression of multiple miRNAs in the progression of cancer cells.

Hepatocellular carcinoma (HCC), a significant challenge for public healthcare systems in developed Western countries including the USA, Canada, and the UK, is influenced by different risk factors including hepatitis virus infections, alcoholism, and smoking. The disruption in the balance of microRNAs (miRNAs) plays a vital function in tumorigenesis, given their function as regulators in numerous signaling networks. These miRNAs, which are mature and active in the cytoplasm, work by reducing the expression of target genes through their impact on mRNAs. MiRNAs are particularly significant in HCC as they regulate key aspects of the tumor, like proliferation and invasion. Additionally, during treatment phases such as chemotherapy and radiotherapy, the levels of miRNAs are key determinants. Pre-clinical experiments have demonstrated that altered miRNA expression contributes to HCC development, metastasis, drug resistance, and radio-resistance, highlighting related molecular pathways and processes like MMPs, EMT, apoptosis, and autophagy. Furthermore, the regulatory role of miRNAs in HCC extends beyond their immediate function, as they are also influenced by other epigenetic factors like lncRNAs and circular RNAs (circRNAs), as discussed in recent reviews. Applying these discoveries in predicting the prognosis of HCC could mark a significant advancement in the therapy of this disease.

Oxygen (O2) supply is constantly maintained by the vascular network for a proper tissue oxygenation. Hypoxia is the result of an increased O2 demand and/or decreased supply and is common in both physiological conditions and human diseases. Angiogenesis is one of the adaptive responses to hypoxia and is mainly regulated by the hypoxia-inducible factors, HIFs. These heterodimeric transcription factors are composed of one of three O2-dependent α subunits (HIF-1, HIF-2, and HIF-3) and a constitutively expressed O2-insensitive subunit (HIF-1β). Among them HIF-1α is the most characterized and its activity is tightly controlled. Under hypoxia, its intracellular accumulation triggers the transcription of several genes, involved in cell survival/proliferation, autophagy, apoptosis, cell metabolism, and angiogenesis. HIF pathway is also modulated by specific microRNAs (miRNAs), thus resulting in the variation of several cellular responses, including alteration of the angiogenic process. The pro-angiogenic activity of HIF-1α is not restricted to endothelial cells, as it also affects the behavior of other cell types, including tumor and inflammatory/immune cells. In this context, exosomes play a crucial role in cell-cell communication by transferring bio-active cargos such as mRNAs, miRNAs, and proteins (e.g., VEGFA mRNA, miR210, HIF-1α). This minireview will provide a synopsis of the multiple factors able to modulate hypoxia-induced angiogenesis especially in the tumor microenvironment context. Targeting hypoxia signaling pathways by up-to-date approaches may be relevant in the design of therapeutic strategies in those pathologies where angiogenesis is dysregulated.