The treatment of congenital deformities, traumatic injuries, infectious diseases, and tumors in the craniomaxillofacial (CMF) region is complex due to the intricate nature of the tissues involved. Conventional treatments such as bone grafts and cell transplantation face limitations, including the need for multiple surgeries, complications, and safety concerns.

This paper aims to provide a comprehensive analysis of the role of exosomes (EXOs) in CMF and dental tissue regeneration and to explore their potential applications in regenerative dental medicine.

An extensive review of advancements in tissue engineering, materials sciences, and nanotechnology was conducted to evaluate the development of delivery systems for EXOs-based therapies. The analysis included how EXOs, as nanovesicles released by cells, can be modified to target specific cells or loaded with functional molecules for drug or gene delivery.

EXOs have emerged as a promising alternative to cell transplant therapy, offering a safer method for cell communication and epigenetic control. EXOs transport important proteins and genetic materials, facilitating intercellular communication and delivering therapeutics effectively. The potential of EXOs in personalized medicine, particularly in diagnosing, customizing treatment, and predicting patient responses, is highlighted.

EXO-mediated therapy holds significant potential for advancing tissue regeneration, offering targeted, personalized treatment options with reduced side effects. However, challenges in purification, production, and standardized protocols need to be addressed before its clinical application can be fully realized.

The impact of exosome-mediated communication between glioblastoma and microglia on the formation of an immunosuppressive microenvironment remains to be explored. Tumor-associated macrophages are more likely to adopt an M2-like phenotype within the immunosuppressive environment. Here, we investigate the molecular mechanisms by which glioblastoma-derived exosomes promote microglial M2 polarization through RAC1.

The expression of RAC1 in GBM was collected from public databases. A C57BL/6 mouse glioma xenograft model was established using intracranial stereotactic injection. RAC1 expression was validated by qRT-PCR, Western blotting, and immunohistochemistry. Glioblastoma-derived exosomes were isolated by ultracentrifugation and characterized by Nanoparticle Tracking Analysis (NTA), transmission electron microscopy, and Western blotting for exosome markers, with the content of RAC1 being profiled. RAC1 and AKT inhibitors were used to co-treat microglia with exosomes. Microglial polarization under different treatment conditions was assessed by Western blotting and immunofluorescence.

Our study reveals that RAC1 is aberrantly expressed in glioblastoma and is associated with macrophage immune infiltration. GBM-derived exosomes, carrying RAC1, promote the M2 polarization of microglia. In microglia treated with GBM-derived exosomes, inhibition of RAC1 activity suppressed AKT phosphorylation and NRF2 nuclear translocation, while reducing the expression of M2 phenotype markers. Notably, following AKT inhibition, the exosome-induced NRF2 nuclear translocation was also significantly suppressed, highlighting the critical role of RAC1-mediated AKT activation in NRF2 translocation and microglial M2 polarization.

Our study demonstrates that RAC1-carrying GBM-exosomes promote M2 polarization of microglia, a process mediated through the RAC1/AKT/NRF2 pathway.

Advancements in exosome isolation technologies are pivotal for transforming personalized medicine and enhancing clinical diagnostics. Exosomes, small extracellular vesicles with diameters ranging between 30 and 150 nm, are secreted into bodily fluids by a variety of cells and play essential roles in intercellular communication. These vesicles facilitate the transfer of nucleic acids, lipids, and proteins, affecting a wide range of biological and pathological processes. Given their importance in disease diagnostics, therapy, and as biomarkers, there has been a surge in developing methods to isolate them from fluids such as urine, saliva, blood, and cerebrospinal fluid. While traditional isolation techniques like ultracentrifugation and polymer-based precipitation have been foundational, recent technological advances have introduced more precise methods like microfluidics and immunoaffinity capture. These newer methods enable high-throughput and specific exosome isolation by targeting surface markers, thus enhancing purity. However, challenges such as balancing purity with yield and the lack of standardized protocols across different laboratories persist, impacting the consistency of findings. By integrating advanced isolation techniques and discussing their implications in diagnostics and therapy, this review aims to catalyze further research and adoption of exosome-based technologies in medicine, marking a significant stride towards tailored healthcare solutions.

Liver cancer or hepatocellular carcinoma (HCC) remains the most common cancer in global epidemiology. Both the frequency and fatality of this malignancy have shown an upward trend over recent decades. Liver cancer is a significant concern due to its propensity for both intrahepatic and extrahepatic metastasis. Liver cancer metastasis is a multifaceted process characterized by cell detachment from the bulk tumor, modulation of cellular motility and invasiveness, enhanced proliferation, avoidance of the immune system, and spread either via lymphatic or blood vessels. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) playing a crucial function in the intricate mechanisms of tumor metastasis. A number of miRNAs can either increase or reduce metastasis via several mechanisms, such as control of motility, proliferation, attack by the immune system, cancer stem cell properties, altering the microenvironment, and the epithelial-mesenchymal transition (EMT). Besides, two other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can competitively bind to endogenous miRNAs. This competition results in the impaired ability of the miRNAs to inhibit the expression of the specific messenger RNAs (mRNAs) that are targeted. Increasing evidence has shown that the regulatory axis comprising circRNA/lncRNA-miRNA-mRNA is correlated with the regulation of HCC metastasis. This review seeks to present a thorough summary of recent research on miRNAs in HCC, and their roles in the cellular processes of EMT, invasion and migration, as well as the metastasis of malignant cells. Finally, we discuss the function of the lncRNA/circRNA-miRNA-mRNA network as a crucial modulator of carcinogenesis and the regulation of signaling pathways or genes that are relevant to the metastasis of HCC. These findings have the potential to offer valuable insight into the discovery of novel therapeutic approaches for management of liver cancer metastasis.

Neurological diseases present a wide range of conditions, intricate diagnosis and treatment processes, and complex prognostic considerations. Therefore, research focusing on the diagnosis and treatment of these diseases is crucial. Exosomal miRNAs are small RNA molecules enclosed in membrane vesicles, released by cells and known to play roles in the development of various neurological disorders. They also serve as specific biomarkers for these conditions. Drawing on extensive research on exosomal miRNAs in diseases like stroke, Alzheimer's, epilepsy, Parkinson's, and neuroregeneration, this paper provides a comprehensive review of the relationship between exosomal miRNAs and neurological diseases. We strive to offer current and detailed theoretical understandings to help with the diagnosis and treatment of these disorders.

Exosomes are nanoscale extracellular vesicles (EVs) secreted by most eukaryotic cells and can be found in nearly all human body fluids. Increasing evidence has revealed their pivotal roles in intercellular communication, and their active participation in myriad physiological and pathological activities. Exosomes' functions rely on their contents that are closely correlated with the biological characteristics of parental cells, which may provide a rich resource of molecular information for accurate and detailed diagnosis of a diverse array of diseases, such as differential diagnosis of Alzheimer's disease, early detection and subtyping of various tumors. As a category of sensitive detection devices, biosensors can fully reveal the molecular information and convert them into actionable clinical information. In this review, recent advances in biosensor-based methods for the detection of exosomes are summarized. We have described the fabrication of various biosensors based on the analysis of exosomal proteins, RNAs or glycans for accurate diagnosis, with respect to their elaborate recognition designs, signal amplification strategies, sensing properties, as well as their application potential. The challenges along with corresponding technologies in the future development and clinical translation of these biosensors are also discussed.

It is known that the transformation of liver cancer-mediated fibroblasts into cancer-related fibroblasts (CAFs) is beneficial to the development of liver cancer. However, the specific mechanism is still unclear.

Human hepatocarcinoma (HepG2) cells were treated with short hairpin RNA (shRNA) of platelet-derived growth factor-D (shPDGF-D) vector, and the exosomes secreted by the cells were separated using ultracentrifugation and identified by using nanoparticle tracking analysis, transmission electron microscope, and western blot analysis. Exosomes were co-cultured with mouse primary fibroblasts, and then the activity, proliferation, cell cycle, migration, epithelial-mesenchymal transition- (EMT-) and CAF marker-related protein expression levels of fibroblasts were determined by cell counting kit-8 (CCK-8), immunofluorescence, flow cytometry, wound healing, real-time reverse transcription-PCR, and western blotting assays, respectively. Co-cultured fibroblasts were mixed with HepG2 cells and injected subcutaneously into mice to construct animal models. The size and weight of xenograft tumor and the expression of epithelial-mesenchymal transition- (EMT-), angiogenesis- and CAFs marker-related proteins were detected.

The exosomes inhibited the proliferation, migration, EMT, and induced cell cycle arrest, as well as decreased the expression of α-SMA, FAP, MMP-9, and VEGF in fibroblasts. In vivo, sh-PDGF-D inhibited tumor growth, reduced the expressions of CD31, vimentin, α-SMA, FAP, MMP9, and VEGF, and promoted the expression of E-cadherin.

Exosomes derived from HepG2 cells transfected with shPDGF-D prevent normal fibroblasts from transforming into CAFs, thus inhibiting angiogenesis and EMT of liver cancer.

Cancer metastasis is a complicated biological process that critically affects cancer progression, patient outcomes, and treatment plans. A significant step in metastasis is the formation of a pre-metastatic niche (PMN). A small subset of cells within tumors, known as cancer stem cells (CSCs), possess unique characteristics including, differentiation into different cell types within the tumor, self-renewal, and resistance to conventional therapies, that enable them to initiate tumors and drive metastasis. PMN plays an important role in preparing secondary organs for the arrival and proliferation of CSCs, thereby facilitating metastasis. CSC-derived exosomes are crucial components in the complex interplay between CSCs and the tumor microenvironment. These exosomes function as transporters of various substances that can promote cancer progression, metastasis, and modulation of pre-metastatic environments by delivering microRNA (miRNA, miR) cargo. This review aims to illustrate how exosomal miRNAs (exo-miRs) secreted by CSCs can predispose PMN and promote angiogenesis and metastasis.

The blood-brain barrier (BBB) presents a major challenge for the effective delivery of therapeutic agents to the brain tumor cells from the peripheral blood circulation, making the treatment of central nervous system (CNS)-related cancers more difficult and resistant to both standard treatments and emerging therapies. Exosomes, which serve as messengers for intercellular communication throughout the body, can naturally or be modified to penetrate the BBB. Recently, exosomes have been increasingly explored as an invasive or non-invasive approach for delivering therapeutic agents to the CNS. With their low immunogenicity, ease of modification, excellent cargo protection, and inherent ability to cross the BBB, exosomes hold great promise for revolutionizing targeted therapy for CNS-related diseases, including brain cancer. In this review, we highlight recent discoveries and insights into the mechanisms exosomes use to penetrate the BBB, the methods they employ to payload diverse therapeutics, and their roles in transporting therapeutic compounds for brain cancer and other neurological disorders.

In this article, we revisit an article, which specifically focuses on the utilization of exosomes derived from human bone marrow mesenchymal stem cells (MSCs) for targeted delivery of gemcitabine in pancreatic cancer treatment. The experimental results demonstrated that the exosome-based drug delivery system derived from MSCs significantly augmented apoptosis in pancreatic cancer cells. The biocompatibility, targeting specificity, and low immunogenicity of exosomes render them as optimal carriers for drug delivery, enabling precise administration of therapeutics to diseased tissues while mitigating adverse effects, thereby achieving targeted treatment of cancer cells and significantly enhancing anti-tumor efficacy. However, the clinical application of exosome drug delivery platforms in oncology still presents challenges, necessitating further optimization to ensure their stability and efficacy. This study focuses on elucidating the advantages of exosomes as a drug delivery platform, exploring the utilization of MSC-derived exosomes in oncology therapy, and discussing their potential and future directions in cancer treatment.

Filopodia are dynamic adhesive cytoskeletal structures that are critical for directional sensing, polarization, cell-cell adhesion, and migration of diverse cell types. Filopodia are also critical for neuronal synapse formation. While dynamic rearrangement of the actin cytoskeleton is known to be critical for filopodia biogenesis, little is known about the upstream extracellular signals. Here, we identify secreted exosomes as potent regulators of filopodia formation. Inhibition of exosome secretion inhibited the formation and stabilization of filopodia in both cancer cells and neurons and inhibited subsequent synapse formation by neurons. Rescue experiments with purified small and large extracellular vesicles (EVs) identified exosome-enriched small EVs (SEVs) as having potent filopodia-inducing activity. Proteomic analyses of cancer cell-derived SEVs identified the TGF-β family coreceptor endoglin as a key SEV-enriched cargo that regulates filopodia. Cancer cell endoglin levels also affected filopodia-dependent behaviors, including metastasis of cancer cells in chick embryos and 3D migration in collagen gels. As neurons do not express endoglin, we performed a second proteomics experiment to identify SEV cargoes regulated by endoglin that might promote filopodia in both cell types. We discovered a single SEV cargo that was altered in endoglin-KD cancer SEVs, the transmembrane protein Thrombospondin Type 1 Domain Containing 7A (THSD7A). We further found that both cancer cell and neuronal SEVs carry THSD7A and that add-back of purified THSD7A is sufficient to rescue filopodia defects of both endoglin-KD cancer cells and exosome-inhibited neurons. We also find that THSD7A induces filopodia formation through activation of the Rho GTPase, Cdc42. These findings suggest a new model for filopodia formation, triggered by exosomes carrying THSD7A.

Exosomes have emerged as pivotal players in precision oncology, offering innovative solutions to longstanding challenges such as metastasis, therapeutic resistance, and immune evasion. These nanoscale extracellular vesicles facilitate intercellular communication by transferring bioactive molecules that mirror the biological state of their parent cells, positioning them as transformative tools for cancer diagnostics and therapeutics. Recent advancements in exosome engineering, artificial intelligence (AI)-driven analytics, and isolation technologies are breaking barriers in scalability, reproducibility, and clinical application. Bioengineered exosomes are being leveraged for CRISPR-Cas9 delivery, while AI models are enhancing biomarker discovery and liquid biopsy accuracy. Despite these advancements, key obstacles such as heterogeneity in exosome populations and the lack of standardized isolation protocols persist. This review synthesizes pioneering research on exosome biology, molecular engineering, and clinical translation, emphasizing their dual roles as both mediators of tumor progression and tools for intervention. It also explores emerging areas, including microbiome-exosome interactions and the integration of machine learning in exosome-based precision medicine. By bridging innovation with translational strategies, this work charts a forward-looking path for integrating exosomes into next-generation cancer care, setting it apart as a comprehensive guide to overcoming clinical and technological hurdles in this rapidly evolving field.

Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.

Despite much research, advances in early prediction of spontaneous preterm birth (sPTB) has been slow. The evolving field of circulating microparticle (CMP) biology may identify novel blood-based, and clinically useful, biomarkers.

To test the ability of a previously identified, 7-marker set of CMP-derived proteins from the first trimester of pregnancy, in the form of an in vitro diagnostic multivariate index assay (IVDMIA), to stratify pregnant patients according to their risk for sPTB.

We employed a previously validated set of CMP protein biomarkers, utilizing mass spectrometry assays and a nested case-control design in a subset of participants from the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b). We evaluated these biomarkers in the form of an IVDMIA to predict risk for sPTB at different gestational ages. Plasma samples collected at 9- to 13-weeks' gestation were analyzed. The IVDMIA assigned subjects to 1 of 3 sPTB risk categories: low risk (LR), moderate risk (MR), or high risk (HR). Independent validation on a set-aside set confirmed the IVDMIA's performance in risk stratification.

Samples from 400 participants from the nuMoM2b cohort were used for the study; of these, 160 delivered<37 weeks and 240 delivered at term. Through Monte Carlo simulation in which the validation results were adjusted based on actual weekly sPTB incidence rates in the nuMoM2b cohort, the IVDMIA stratifications demonstrated statistically significant differences among the risk groups in time-to-event (birth) analysis (P<.0001). The incidence-rate adjusted cumulative risks of sPTB at ≤32 weeks' gestation were 0.4%, 1.6%, and 7.5%, respectively for the LR, MR, and HR groups, respectively. Compared to the LR group, the corresponding risk ratios of the IVDMIA assigned MR and HR group were 4.25 (95% confidence interval [CI] 2.2-7.9) and 19.92 (95% CI 10.4-37.4), respectively.

A first trimester CMP protein biomarker panel can be used to stratify risk for sPTB at different gestational ages. Such a multitiered stratification tool could be used to assess risk early in pregnancy to enable timely clinical management and interventions, and, ultimately, to enable the development of tailored care pathways for sPTB prevention.

Mononuclear phagocytes (MPs), which consist of dendritic cells, monocytes, and macrophages, are distributed throughout the body and actively eliminate invading microorganisms and abnormal cells. Depending on the local microenvironment, MPs manifest considerably various lifespans and phenotypes to maintain tissue homeostasis. Vascular-associated mononuclear phagocytes (VaMPs) are the special subsets of MPs that are localized either within the lumen side or on the apical surface of vessels, acting as the critical sentinels to recognize and defend against disseminated tumor cells. In this review, we introduce three major types of VaMPs, patrolling monocytes, Kupffer cells, and perivascular macrophages, and discuss their emerging roles in immunosurveillance during incipient metastasis. We also explore the roles of lineage-determining transcription factors and cell surface receptors that endow VaMPs with potent anti-tumor activity. Finally, we highlight the molecular and cellular mechanisms that drive the phenotypic plasticity of VaMPs and summarize combinatory strategies for targeting VaMPs in overt metastasis.

Aberrant endometrial collagen I deposition during the implantation window impairs endometrial stromal cell (ESC) decidualization, which may contribute to lower pregnancy rate in endometriosis (EMs) patients with in vitro fertilization (IVF) treatment. However, the underlying mechanism of eutopic aberrant endometrium collagen I deposition in EMs remains unclear. In this study, we found increased endometrial collagen I and defective decidualization in the mid-secretory phase of EMs patients, while the level of eutopic ESCs' autophagy was decreased, which was an important mechanism of intracellular collagen degradation. Lower ESCs' autophagy level may cause the endometrial collagen I deposition in EMs. Furthermore, in vivo and in vitro studies showed that the extracellular vesicles derived from the ectopic ESCs of EMs patients (EMs-EVs) encapsulated higher PKM2 inhibited autophagy of the ESCs accompanied by an increase of collagen I. We also found that the constructed EMs-EVsAd-PKM2 with PKM2 overexpression inhibited ESCs' autophagy by activating the Akt/mTOR signaling pathway. And the expressions of PKM2, p-Akt and p-mTOR were also increased in the endometrium of EMs patients. Collectively, these data showed that EMs-EVs delivering PKM2 inhibited autophagy inducing aberrant endometrial collagen I deposition via the Akt/mTOR signaling pathway to impair decidualization, which provided a potential therapeutic target for improving the IVF pregnancy rate in EMs patients.

Chemotherapy is important in the systemic therapy for breast cancer. However, after chemotherapy, the left living tumour cells are more progressive. There is an urgent need to study the underlying mechanism which is still unclear to further improve the therapeutic efficacy of chemotherapy in breast cancer. Here we find a pro-tumour effect of the apoptotic cells induced by the chemotherapy, which is mediated by a new subset of macrophages undergoing LC3-associated phagocytosis (LAP). By transferring exosomal S100A11 into the living tumour cells after chemotherapy, the macrophage exhibits a more pro-tumour phenotype than classic M2-type macrophages. Moreover, S100A11 binds to IFITM3, inducing Akt phosphorylation of living tumour cells after chemotherapy, which promotes tumour progression. Of note, Akt inhibitor can enhance the therapeutic effcicay of chemotherapy in breast cancer. This study provides a novel mechanistic link between tumour-associated macrophages and breast cancer, uncovering Akt as a potential therapeutic target to improve chemotherapy efficacy.

Natural killer (NK) cell-derived exosomes (NK-Exos) are emerging as a promising avenue in cancer immunotherapy due to their inherent tumor-targeting properties and their capacity to deliver therapeutic agents directly to malignant cells. This research delves into the boosted anti-tumor potency of NK-Exos that has been genetically enhanced to overexpress NKG2D, a vital activating receptor, along with interleukin-24 (IL24), a cytokine renowned for its selective suppressive impact on tumor cells. NKG2D facilitates the recognition of tumor cells by binding to stress-induced ligands, while IL24 induces apoptosis and modulates immune responses to enhance tumor destruction. The NK-Exos engineered to express both NKG2D and IL24 significantly enhanced tumor targeting and increased the apoptosis rate of tumor cells by 30% in A549 and by 20% in HELA at 48 h compared with non-modified NK-Exos, respectively. Furthermore, this enhancement also impacted cell proliferation, with inhibition rates increasing by 30%, 15%, and 15% in A549, HELA, and MCF-7 cells, respectively, and it reduced A549 cell migration by 10%. The integration of NKG2D and IL24 within NK-Exos confers a dual therapeutic mechanism, synergistically amplifying their efficacy in cancer treatment. The utility of NK-Exos co-expressing NKG2D and IL24 offers a novel approach to overcome the limitations of current therapies, providing prolonged tumor suppression and precise targeting of malignant cells and holding great promise for clinical application.

Tumor-associated macrophages (TAM) are critical elements of intercellular communication in tumor microenvironment (TME), and exosomes are key mediators between tumor cells and the TME. According to previous reports, miRNAs exert a pivotal role in ovarian cancer (OC) development. The purpose of this work was to explore the function of TAM-derived exosomal miR-589-3p in OC development and elucidate the underlying molecular mechanisms.

First, peripheral blood mononuclear cells (PBMC) were treated with IL-4 and IL-13 to polarize them into M2-type macrophages. Exosomes were separated from M2-type macrophages, and the physical properties of exosomes were evaluated using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Next, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was applied to examine the expression of relevant genes. Subsequently, Targetscan and miRDB were utilized to predict miR-589-3p target genes, and then the interaction between miR-589-3p and BCL2L13 was verified by dual luciferase assay and RNA Binding Protein Immunoprecipitation (RIP) assay. Finally, Cell Counting Kit-8 (CCK-8) and flow cytometry experiments were employed to explore the changes in the proliferative and apoptotic abilities of OC cells.

In this research, we demonstrated that TAM-derived exosomes facilitated OC cell proliferation and suppressed OC cell apoptosis. Then, qRT-PCR results indicated that miR-589-3p were markedly elevated after co-culture of TAM-derived exosomes with OC cells. In addition, we discovered that miR-589-3p was bound to BCL-2-like protein 13 (BCL2L13), which was confirmed through luciferase assay and RIP assay. Furthermore, functional analysis displayed that TAM-derived exosomes treated with miR-589-3p inhibitor attenuated the promotion of OC cell progression by exosomes.

TAM-derived exosomal miR-589-3p enhanced OC progression through BCL2L13, which offers a novel for OC therapy.

Colorectal cancer liver metastases (CRLM) are the primary cause of mortality in colorectal cancer (CRC) patients, highlighting the importance of understanding the underlying mechanisms. The tumor microenvironment (TME) and its interaction with tumor cells play a crucial role in CRLM progression. Notably, the stability and peak levels of tumor-derived exosomal miRNAs facilitate intercellular communication in the TME. Hepatic stellate cells (HSCs), key liver mesenchymal cells, constitute about 33% of the liver's nonsolid cell population and exhibit plasticity. However, the specific role of tumor-derived exosomal miRNAs in the crosstalk between HSCs and tumor cells during the CRLM process remains unclear. We studied CRC-secreted exosomal miR-1246 and its impact on HSCs, as well as its effects on CRC cell proliferation and metastasis. Our findings demonstrate that CRC-secreted exosomal miR-1246 can be internalized by HSCs, leading to their activation and facilitating the metastatic potential of CRC cells. Mechanistically, exosomal miR-1246 targets INSIG1, resulting in SREBP2 nucleation and cholesterol metabolism alterations. This accumulation of free cholesterol (FC) regulates the TLR4/NF-κB/TGF-β pathway, promoting HSC activation. Activated HSCs, in turn, enhance liver metastasis of CRC cells through the TNFSF13/TNFRSF13B axis. Our study reveals the role of CRC-secreted exosomal miR-1246 in triggering HSC activation and reprogramming the TME, ultimately facilitating liver metastasis in CRC patients. Exosomal miR-1246 could serve as a potential non-invasive biomarker for predicting colorectal cancer liver metastasis, enhancing our understanding of CRC-associated liver metastases.

Bronchial asthma (asthma) is a chronic inflammatory disease of the airways that remains an unresolved problem. Reportedly M2 macrophages and exosomes play a role in inflammation, including asthma. We investigated the roles of M2 macrophage-derived exosomes (M2-Exos) effect in asthmatic progression by using ovalbumin (OVA) induced asthmatic mice model. M2-Exos significantly ameliorated the pulmonary inflammatory response and airway hyperresponsiveness in asthmatic mice and suppressed aberrant proliferation and transient receptor potential polycystic protein 2(TRPP2) expression in LPS-stimulated primary airway smooth muscle cells (ASMCs). Then, we found that miR-186-5p of M2-Exos could target TRPP2 through online database analysis. However, miR-186-5p downregulation by miR-186-5p inhibitors decreased the protective effect of M2-Exos in asthmatic mouse and cellular models. miR-186-5p was identified and selectively combined with the polycystin-2 gene encoding TRPP2 protein, inhibited TRPP2 protein production, and downregulated TRPP2 expression. A reduction in the number of TRPP2 calcium (Ca) channels formed on the cell membrane leads to a decreased intracellular Ca2+ concentration ([Ca2+] i), causing reduced ASMC contraction and proliferation, thereby improving airway hyperresponsiveness and airway remodeling in asthma. Collectively, we conclude that M2 exosomal miR-186-5p to alleviate asthma progression and airway hyperresponsiveness though downregulating TRPP2 expression. These results may offer a novel insight to the treatment and drug delivery of asthma.

Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures released by cells into the extracellular milieu. These vesicles encapsulate a diverse array of molecular constituents, including nucleic acids, proteins, and lipids, which provide insights into the physiological or pathological conditions of their parent cells. Despite their potential, the study of EV-derived DNA (EV-DNA) has gathered relatively limited attention. This review aims to present a thorough examination of the emerging knowledge surrounding the utility of EV-DNA as a non-invasive biomarker across a spectrum of diseases. The review delves into various mechanisms underlying DNA packaging within EVs and the prevalent methodologies employed for extraction of EV-DNA. The relevance of EV-DNA is assessed across numerous health conditions, notably cancer, cardiovascular diseases, neurodegenerative disorders, infectious diseases, and pregnancy-related complications. The use of EV-DNA for cancer mutation detection has demonstrated remarkable sensitivity and specificity, thereby enhancing both diagnostic accuracy and therapeutic monitoring. In the context of cardiovascular diseases, EV-DNA serves as a predictive marker for events such as myocardial infarctions and shows a correlation with the severity of the disease. With respect to neurodegenerative conditions, including Parkinson's and Alzheimer's, EV-DNA contributes to the understanding of disease mechanisms and progression. Additionally, it plays an essential role in modulating immune tolerance and facilitating communication between maternal and fetal systems. Although there is a pressing need for standardized protocols for EV isolation and DNA analysis to facilitate clinical implementation, the prospect of EV-DNA as a non-invasive biomarker for diagnostic and prognostic purposes across diverse pathological conditions is considerable.

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.

Exosomes are communication carriers and suitable biomarker candidates due to their cargoes with specific dynamic profiles. Integrins, as valuable prognostic markers in cancer, have importance in exosome-cell interaction. However, the role of exosome integrins in chemoresistant colorectal cancer remained unclear.

Oxaliplatin- and 5-FU-resistant cells (OXR and FUR) were established from human HCT-116 cells of colorectal cancer. Exosomes were collected from untreated and treated cells with oxaliplatin or 5-FU. Exosomes were isolated via ultracentrifugation and characterized using DLS and electron microscopy to evaluate size and morphology. Western blot analysis was employed to identify exosomal markers. The effects of exosomes on parental cells were examined using various methods, including MTT assay for proliferation, wound healing assay for migration, flow cytometry for cell cycle and apoptosis analysis, Matrigel-coated transwell inserts for invasion, and western blot for integrin expression evaluation.

Exosome integrins determine resistance behaviors in cells. We observed that exosomes from OXR cells or OXR cells treated with oxaliplatin increased ITGβ3 expression and decreased ITGβ4 expression in parental cells, resulting in distinct resistance behaviors. Exosomes from FUR cells or FUR cells treated with 5-FU reduced ITGβ4 levels and elevated ITGαv levels in parental cells, leading to varying degrees of invasive resistance behaviors. These findings suggest that exosome integrins may affect these behaviors. High ITGβ3 exosomes induced oxaliplatin resistance behaviors in parental cells. Lowering ITGβ3 levels in these exosomes inhibited the resistance behaviors observed in these cells. FUR exosomes that overexpressed ITGαv or ITGβ4 resulted in invasive 5-FU resistance behaviors in parental cells. A reduction in these exosome integrin levels led to moderate invasive behaviors. The decrease of ITGβ4 in FUR cell exosomes inhibited resistant migration and proliferation in parental cells. A twofold reduction of ITGαv in FUR cell exosomes resulted in a threefold decrease in invasion and inhibited migration in parental cells compared to those treated with high ITGαv exosomes.

Our findings reveal that, despite discrepancies between cellular integrin patterns and cellular behaviors, the levels of exosomal ITGβ3, ITGαv, or ITGβ4 could serve as potential diagnostic and therapeutic markers for resistance to oxaliplatin and 5-FU in future cancer treatments.

The leading form of cancer affecting females globally is breast cancer, characterized by an unregulated growth of cells within the breast. Therefore, examining breast tissue is crucial in accurately identifying and treating this disease. Exosomes are very small enclosures bounded by a layer of cells and produced by a variety of cells present in the cancerous tissue surroundings. They play a crucial role in several biological functions in cancerous tumors. These exosomes carry non-coding RNAs (ncRNAs) and are discharged into the TME, where they are instrumental in the development and advancement of tumors. Additionally, the ncRNAs enclosed in exosomes act as significant mediators of communication within cells. Consequently, there is limited comprehension regarding the precise roles and targets of exosomal RNA in regulation, as research in this area is still in its preliminary phases. This piece provides a comprehensive overview of the latest studies on exosomes, delving into their impact on the behavior of cancer cells and immune cells. Moreover, it presents a compilation of the diverse forms of non-coding RNA molecules found in exosomes released by both cancerous and supportive cells, including circular RNAs, microRNAs, and long non-coding RNAs. Current research has proven the noteworthy influence that non-coding RNA molecules have on the progression, proliferation, drug resistance, and immune responses of breast cancer cells.

Pancreatic adenocarcinoma (PAAD) is a fatal disease with poor survival. Increasing evidence show that hypoxia-induced exosomes are associated with cancer progression. Here, we aimed to investigate the function of hsa_circ_0007678 (circR3HCC1L) and hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD progression. Through the exoRBase 2.0 database, we screened for a circular RNA circR3HCC1L related to PAAD. Changes of circR3HCC1L in PAAD samples and cells were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, migration, invasion were analyzed by colony formation, cell counting, and transwell assays. Measurements of glucose uptake and lactate production were done using corresponding kits. Several protein levels were detected by western blotting. The regulation mechanism of circR3HCC1L was verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Exosomes were separated by differential ultracentrifugation. Animal experiments were used to verify the function of hypoxia-derived exosomal circR3HCC1L. CircR3HCC1L was upregulated in PAAD samples and hypoxic PAAD cells. Knockdown of circR3HCC1L decreased hypoxia-driven PAAD cell proliferation, migration, invasion, and glycolysis. Hypoxic PAAD cell-derived exosomes had higher levels of circR3HCC1L, hypoxic PAAD cell-derived exosomal circR3HCC1L promoted normoxic cancer cell malignant transformation and glycolysis in vitro and xenograft tumor growth in mouse models in vivo. Mechanistically, circR3HCC1L regulated pyruvate kinase M2 (PKM2) expression via sponging miR-873-5p. Also, PKM2 overexpression or miR-873-5p silencing offset circR3HCC1L knockdown-mediated effects on hypoxia-challenged PAAD cell malignant transformation and glycolysis. Hypoxic PAAD cell-derived exosomal circR3HCC1L facilitated PAAD progression through the miR-873-5p/PKM2 axis, highlighting the contribution of hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD.

Approximately one-third of advanced renal cell carcinoma (RCC) patients develop osteolytic bone metastases, leading to skeletal complications. In this review, we first provide a comprehensive perspective of seminal studies on bone metastasis of RCC describing the main molecular modulators and growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction. We next focus on newer developments revealing with in-depth details, the bidirectional interplay between renal cancer cells and the immune and stromal microenvironment that can through epigenetic reprogramming, profoundly affect the behaviors of transformed cells. Understanding their mechanistic interactions is of paramount importance for advancing both fundamental and translational research. These new investigations into the landscape of RCC-bone metastasis offer novel insights and identify potential avenues for future therapeutic interventions.

Heterogeneous roles of complement C3 have been implicated in tumor metastasis and are highly context dependent. However, the underlying mechanisms linking C3 to tumor metastasis remain elusive in renal cell carcinoma (RCC). Here, we demonstrate that C3 of RCC cell-derived extracellular vesicles (EVs) contributes to metastasis via polarizing tumor-associated macrophages (TAMs) into the immunosuppressive phenotype and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, EV C3 induces the secretion of CCL2 and CXCL1 by lung macrophages and subsequently enhances TAM polarization and PMN-MDSC recruitment. Notably, targeting the CCL2/CCR2 or CXCL1/CXCR2 axis with the inhibitors RS504393 or Navarixin, respectively, effectively suppresses lung metastasis induced by RCC-derived C3 in a mouse model. Clinically, RCC patients with high expression of C3 demonstrate poor prognosis. Collectively, our findings reveal that tumor-derived EV C3 induces an immunosuppressive tumor microenvironment via TAMs, and thus promoting RCC metastasis.

Previous studies have found that dyslipidemia is a risk factor for pancreatic cancer (PC), and that lipid-lowering drugs may reduce the risk of PC. However, it is not clear whether dyslipidemia causes PC. The Mendelian randomization (MR) study aimed to investigate the causal role of lipid traits in pancreatic cancer and to assess the potential impact of lipid-lowering drug targets on pancreatic cancer. Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for PC were obtained from an independent GWAS datasets. Colocalization analyses were performed to validate the robustness of the results. No significant effect of lipid-lowering drug targets on PC risk was found. Genetic mimicry of lipoprotein lipase (LPL) was potentially associated with PC risks. Significant MR associations were observed in the discovery dataset (OR 1.64 [95% CI 1.24-2.16], p = 4.48*10-4) with PC in one dataset. However, the finding was not verified in the replication dataset. Our findings do not support dyslipidemia as a causal factor for PC. Among lipid-lowering drug targets, LPL is the potential drug target in PC.

Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal circRNAs in gastric cancer (GC) progression has not been completely clarified.

The exosomal circRNAs enriched in GC were identified using exosomal circRNA sequencing. The biological function of circMAN1A2 in GC was investigated using a series of in vitro and in vivo experiments. PKH-67 staining was used to label the exosomes. The molecular mechanism of exosomal circMAN1A2 was investigated via mass spectrometry, immunoprecipitation, Western blot, and single-cell RNA-sequencing data analyses.

In our study, we determined that circMAN1A2 (hsa_circ_0000118) was enriched in GC-derived exosomes. Higher circMAN1A2 expression was related to poor survival in GC patients (HR = 2.917, p = 0.0120). Exosomal circMAN1A2 promoted GC progression in vitro and in vivo and suppressed the antitumour activity of T cells. Moreover, circMAN1A2 bound to SFPQ in GC cells and T cells, promoting the G1/S phase transition of the cell cycle in GC cells while inhibiting the activation of the T cell receptor signalling pathway in T cells to decrease antitumour activity. Mechanistically, circMAN1A2 competed with FBXW11 for binding to SFPQ, preventing FBXW11-mediated k48-linked ubiquitination and SFPQ protein degradation, thereby stabilizing SFPQ expression.

Our work confirms the critical role of exosomal circMAN1A2 in the progression and immunosuppression of GC. This novel axis of circMAN1A2-SFPQ provides new insights into exosomal circRNA-based GC diagnostic and therapeutic strategies.

Hyaluronan (HA) is a critical component of cell and tissue matrices and an important signaling molecule. The enzymes that synthesize and process HA, as well as the HA receptors through which the signaling properties of HA are transmitted, have been identified in extracellular vesicles and implicated in context-specific processes associated with health and disease. The goal of this review is to present a comprehensive summary of the research on HA and its related receptors and enzymes in extracellular vesicle biogenesis and the cellular responses to vesicles bearing these extracellular matrix modulators. When present in extracellular vesicles, HA is assumed to be on the outside of the vesicle and is sometimes found associated with CD44 or the HAS enzyme itself. Hyaluronidases may be inside the vesicles or present on the vesicle surface via a transmembrane domain or GPI linkage. The implication of presenting these signals in extracellular vesicles is that there is a greater range of systemic distribution and more complex delivery media than previously thought for secreted HA or hyaluronidase alone. Understanding the context for these HA signals offers new diagnostic and therapeutic insight.

Augmented extracellular matrix (ECM) stiffness is a mechanical hallmark of cancer. Mechanotransduction studies have extensively probed the mechanisms by which ECM stiffness regulates intracellular communication. However, the influence of stiffness on intercellular communication aiding tumor progression in three-dimensional microenvironments remains unknown. Small extracellular vesicles (EVs) are communicators of altered biophysical cues to distant sites through EV-ECM interactions and EV-mediated recipient cell-ECM interactions. Here we demonstrate stiffness-mediated modulation of small EVs secretion and cargo from three-dimensional oral squamous cell carcinoma spheroids. Using a spheroid culture platform with varying matrix stiffness properties, we show that small EVs carry parental biomolecular cargo, including mechanosensitive Piezo1 ion channel and adhesion molecule CD44. We comprehensively validate the presence of both markers in our EV populations using proteomic and genetic analysis. Transcriptomic analysis of microRNA and long non-coding RNA cargo of small EVs released from soft and stiff ECM spheroids revealed enrichment of tumorigenic and metastatic profiles in EVs from stiff ECM cultures compared to that of soft ones. Gene set enrichment analysis of a comparative dataset obtained by overlaying spheroid mRNA and EV miRNA profiles identified key oncogenic pathways involved in cell-EV crosstalk in the spheroid model.

Peritoneal carcinomatosis (PC) in gastric adenocarcinoma (GAC) is the most common metastatic site and leads to a short median survival. Exosomes have been shown to remodel the microenvironment, facilitating tumor metastases. However, the functional component in GAC cell-derived exosomes that remodel the landscape in the peritoneal cavity remains unclear. To address this, we performed in-depth proteomic profiling of ascites-derived exosomes from patients with PC, and we found that Galectin-3 was highly enriched in exosomes derived from malignant ascites. exosomal Galectin-3 was the crucial regulator of PC. Blockage of exosomal Galectin-3 significantly inhibited tumor metastases and prolonged overall survival. Exosomal Galectin-3 activated cancer-associated fibroblasts through integrin α1β1/FAK/Akt/mTOR/CXCL12 signaling. Combined inhibition of the CXCL12-CXCR4 axis and exosomal Galectin-3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly diminished PC progression and durable antitumor responses. These findings provide a rationale for clinical strategy of targeting exosomal Galectin-3 to treat PC.

This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.

Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelium of the nasopharynx. Given its late diagnosis, NPC raises serious considerations in Southeast Asia. In addition to resistance to conventional treatment that combines chemotherapy and radiation, NPC has high rates of metastasis and frequent recurrence. Exosomes are small membrane vesicles at the nanoscale that transport physiologically active compounds from their source cell and have a crucial function in signal transmission and intercellular message exchange. The exosomes detected in the tissues of NPC patients have recently emerged as a potential non-invasive liquid biopsy biomarker that plays a role in controlling the tumor pathophysiology. Here, we take a look back at what we know so far about the complex double-edged sword role of exosomes in NPC. Exosomes could serve as biomarkers and therapeutic agents, as well as the molecular mechanisms by which they promote cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance, and chemotherapy resistance in NPC. Furthermore, we go over some of the difficulties and restrictions associated with exosome use. It is anticipated that this article would provide the reference for the apply of exosomes in clinical practice.

A recent study revealed the oncogenic role of box C/D small nucleolar RNA 52 (SNORD52) in hepatocellular carcinoma (HCC) by facilitating the aggressive phenotypes of hepatoma cells. However, the potential role of exosomal SNORD52 in macrophage polarization during HCC progression remains poorly understood.

Exosomes were isolated from hepatoma cells. Western blotting and flow cytometry were performed to determine the levels of M2 macrophage polarization markers. SNORD52 expression was assessed using qRT-PCR. The levels of JAK2/STAT6 pathway-related proteins were analyzed using western blotting.

SNORD52 was enriched in exosomes derived from hepatoma cells and in plasma samples from patients with HCC. Hepatoma cell-derived exosomal SNORD52 was internalized by THP-1 macrophages. SNORD52 overexpression increased the levels of M2 macrophage polarization markers and JAK2/STAT6 pathway-related proteins Additionally, hepatoma cell-derived exosomal SNORD52 interacted with the JAK2/STAT6 pathway to mediate M2 macrophage polarization.

Our findings revealed that hepatoma cell-derived exosomal SNORD52 induces M2 macrophage polarization by activating the JAK2/STAT6 pathway.

Cancer-associated fibroblasts (CAFs) constitute a critical component of the tumor microenvironment (TME). CAFs can be reprogrammed by cancer cells, leading to the production of extracellular vesicles (EVs). These EVs serve as carriers for bioactive substances, including proteins, nucleic acids, and metabolic products, thereby facilitating tumor progression. CAF-derived EVs exert substantial influence on tumor cell proliferation, invasion, and metastasis, the immunological environment, and the processes of lymphangiogenesis and angiogenesis. Despite their potential as non-invasive biomarkers and therapeutic delivery vehicles, the clinical application of CAF-derived EVs is currently limited by challenges in purification and precise targeting. This review delineates the diverse roles of CAF-derived EVs in tumor growth, metastasis, and immune evasion within the TME.

Leuconostoc mesenteroides is a lactic acid bacteria found in fermented products. In our previous study, L. mesenteroides was isolated from Camellia japonica flowers, and its acid tolerance and antibacterial properties were thoroughly investigated. This study focuses on the inhibition of melanin synthesis and inflammation of exosomes derived from L. mesenteroides. Moreover, L. mesenteroides exosomes (DB-14 exosome) exhibited significant inhibitory effects on inflammation and melanogenesis. At concentrations of 4.44 × 108, 8.88 × 108, and 1.78 × 109 particles/ml, the exosomes reduced nitric oxide and prostaglandin E2 activity while maintaining the growth of RAW 264.7 macrophages. In addition, proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha, were rarely expressed, and western blot revealed that L. mesenteroides DB-14 derived exosomes inhibited inducible nitric oxide synthase and cyclooxygenase-2 expression. Moreover, the exosomes had no toxic effects on B16F10 melanoma cells at concentrations of 1.78 × 109, 3.55 × 109, and 7.10 × 109 particles/ml, and they suppressed melanogenesis by reducing tyrosinase activity. Furthermore, western blot analysis demonstrated that microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase related protein (TRP)-1, and TRP-2 were evidently reduced, ultimately repressing melanin production. Moreover, MITF expression was inhibited by reduced mitogen-activated protein kinase and protein kinase B phosphorylation levels. Overall, this study proves the efficacy of the novel DB-14 exosome as a strong lightening and anti-inflammatory agent.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.