Abstract
The clinical translation of safe and effective therapeutic methods for brain cancer treatment is a major challenge that persists in modern medicine. The insufficient drug delivery into the regime of the affected brain tissue due to blood–brain barrier (BBB) restriction leads to a poor prognosis of the disease. However, an alternative strategy using biomaterials like exosomes can offer advancements in the treatment of brain cancer. Exosomes are a type of extracellular microvesicle with a diameter of 30–100 nm, principally functioning as intercellular mediators in the cell signaling process. Due to their biological origin, exosomes demonstrate a significant ability to cross the BBB and possess enhanced biocompatibility, high drug-loading capacity, and low immunogenicity. With the innate property of biomolecule delivery, exosomes also offer enhanced cellular uptake, rendering them exceptional in drug delivery systems. Herein, we focus on the anticancer and diagnostic applications of exosomes for brain cancer therapeutics. The enhancement of the physico-chemical properties of various cell-derived exosomes can be effectively used as a prime drug delivery agent in most treatment strategies. The biphasic and fast drug release in acidic pH of the tumor microenvironment by exosome-mediated drug delivery system contributes to passive targeting, which is often considered advantageous over other drug delivery platforms. These characteristic features are likely to enhance the therapeutic potential and efficacy of the treatment. The exosome loaded with the drug acts as an efficient biomaterial to surpass the BBB, followed by efficient cellular uptake, leading to cytotoxicity in glioblastoma cells. In this review, we summarize the recent updates in theranostic and prognostic strategies using exosomes as a mediator and their prevalence in biomedical applications, with a focus on brain cancer diseases.
1 Introduction
Exosomes are nanoscale extracellular vesicles, typically 40–100 nm in diameter, distinguished by their well-defined physicochemical properties. They play a pivotal role in intercellular communication through the transfer of bioactive molecules and modulating key cell signaling pathways (1). The bio-generated exosomes secreted by cells after fusing with multivesicular bodies are released into the extracellular matrix. They further transcend to neighboring or distinct cells, promote the delivery of information in the form of proteins, lipids, and Ribonucleic acid (RNA), which involves de novo transcriptional and translational changes in the host cells (2). Exosomes are readily found in most extracellular fluids, both in physiological and pathological conditions (3). The isolation of exosomes involves classical differential ultracentrifugation and density gradient ultracentrifugation (4, 5), size-based isolation or ultrafiltration (6), microfluidics-based isolation (7), exosome precipitation (8), and immune-affinity-based capture (9) from the body fluids. The intrinsic functional property of exosomes in transferring material through the cells evidently increases cellular uptake (10) in both in vitro and in vivo systems. Moreover, the enhanced biocompatibility of biologically derived exosomes (11), as well as the better transfer of cargo to the cell, and the abundance of body fluids, relatively increase the implementation of exosomes in the drug delivery system. The ease of isolation and biological source of origins are also contributing much to the successful employment and providing a better platform in the drug delivery system.
The blood–brain barrier (BBB) is a distinguishable lining boundary of cells in the vasculature of brain tissue, functioning as a highly selective barrier that separates blood and brain fluid. BBB primarily regulates and directs the nutrients and other essential biomolecules (12) to the brain. For a successful treatment of brain tissue-related diseases, the therapeutics should reach the regime of the brain tissue. However, the strict nature of the BBB restricts therapeutics from crossing the barrier, resulting in a poor prognosis of the disease. The bioavailability of biomolecules, drugs, small molecules, and other metabolites in the brain is often poor due to functional aspects of the BBB (13, 14). To address this issue, the practice of ultrasound and other strategies temporarily opens the BBB, which yields a surpass of the drugs/payloads across the barrier, leaving structural impairment to the BBB (15). Traditional drug delivery system has certain disadvantages, including low accumulation and bioavailability in target cells, off-target toxicity, and quick elimination, which restricts their therapeutic interventions (16). Thus, a controllable and non-harmful way of transporting the cargos across the BBB is the need of the hour. Nanoparticle-based delivery approaches have been found to be ideal in this scheme with enhanced efficiency and potent targeting to the specified location.
Over the past few decades, numerous synthetic delivery vectors, including liposomes, polymer micelles, inorganic nanoparticles, and dendrimers, have been synthesized to address these difficulties in clinical translation. Liposomes are one of the effective and clinically authorized vectors in the nanoparticle domain currently available (17). Liposomes are bi-layered membranes made of lipids, which are effective in loading hydrophilic drugs into the liposome lumen. When engineered, targeting ligands can be added to improve tissue uptake. Although liposomes are lipid-soluble, due to the size and the presence of tight junctions between BBB cells, liposomes are restricted from easily diffusing across the BBB (18). To get across the BBB, they must instead use certain transport mechanisms or techniques like ultrasound-mediated delivery (19). Polymeric nanoparticles, inorganic nanoparticles, and dendrimers also confront several obstacles, such as the lack of organ-specific targeting, physical and chemical traits associated with toxicity, and an adverse immune response (20), also contributing to deficiencies in the imperative cellular uptake and BBB crossing to treat brain cancer.
Exosomes, also known as natural nanoparticles, are best suited for drug delivery applications in brain-related diseases. The first discovery of exosomes dates back over 25 years, when researchers found the formation of extracellular vesicles, involved in the selective externalization of the transferrin receptor (16). However, exosomes can acquire a higher degree of complexity in individual components; they are rich in phospholipids, cholesterol, and sphingomyelin. Furthermore, extra binding sites for drug loading may occur in exosomes due to biomolecules present in the membrane and core (20). In recent years, there has been a multi-fold increment in the successful implementation of exosomes as a drug delivery vehicle in biomedical research. The increasing attention in exosome research highlights its unique physico-chemical properties as a natural nanoparticle and has revolutionized the diagnostic and therapeutic regime in brain cancer patients. Yang et al. reported a drug delivery system with exosomes for doxorubicin (Dox) across the BBB in zebrafish (Danio rerio) model, with improved cellular uptake of the drug (21). The exosomes encapsulate therapeutic payloads, such as chemotherapeutic drugs and biomolecules, warranting the effective delivery to the brain tissues, enabling local therapeutic effects while reducing non-specific and systemic side effects (18, 19). The biological origin and composition of exosomes improve the immune tolerance and increase biocompatibility compared to synthetic nanocarriers (22). Furthermore, exosomes can be considered a prime contender in the diagnosis of diseases through various biomarkers in brain cancer conditions, by non-invasive methods (from body fluids such as sweat, urine, and saliva) or other modes like liquid biopsies. Moreover, the application of surface-engineered exosomes as therapeutic carriers has emerged as a promising strategy to unravel the limitations of conventional drug delivery systems. By exploiting the intrinsic cellular uptake and circulation mechanisms of exosome-derived pathways, this approach enhances the multitude of targeted drug delivery and therapeutic applications (23).
2 Materials and methods
In this review, we conducted a comprehensive literature review and gathered relevant studies for the evidence synthesis. A detailed methodology, which was utilized for the search strategy and inclusion/exclusion criteria, is elaborated in the following sub-sections.
2.1 Study design
This review focuses on the current updates in the therapeutic and diagnostic implications of exosomes in brain cancer research and clinical manifestations. This review aims to provide a concise yet comprehensive literature review of the latest advancements and emerging insights into the role of exosomes in the diagnosis, prognosis, and therapeutic interventions for brain cancers, with a special emphasis on glioblastoma and glioma.
2.2 Sources database and search strategy
A search for a comprehensive literature survey was conducted in electronic databases, including PubMed, Web of Science (Core Collection), and Scopus. The detailed search strategies for each database are described in Supplementary Table S1.
2.3 Inclusion and exclusion criteria
To establish a comprehensive literature review, we performed a search strategy using the keywords and related Medical Subject Headings (MeSH) terms for “brain cancer,” “glioblastoma,” and “exosomes.” We restricted the search to original articles and review articles on exosomes and brain cancer. This search was restricted to peer-reviewed articles published in only English-language journals between 2009 and 2024. The editorials, case reports, conference abstracts, dissertations, gray literature, and non-English language articles were excluded from evidence synthesis.
3 Exosomes in brain cancer disease progression
Exosomes impart in the regulatory mechanism of pathological angiogenesis, including tumor angiogenesis by actively delivering pro-angiogenic biomolecules like matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and other microRNAs (24). In a tumor microenvironment, the intra-tumoral hypoxia evidently stimulates angiogenesis and led to improved uptake of tumor derived exosomes. Hypoxia-induced cell signaling in cancer cells is mediated by exosomes (25) and affects tumor growth and metastasis. Due to the protective and selective nature of the BBB, brain metastasis presents a unique challenge in prognosis. However, tumor-derived exosomes are intermediate between the cancer microenvironment and that of healthy tissues in the brain. This further enhances the aggressiveness of the disease, thereby halting the remission. It was observed that tumor-derived exosomes can alter the BBB, promoting an environment favorable for developing secondary tumors at the site (26). Moreover, exosomes carrying specific miRNAs, which regulate cellular responses and modulate tumor-stroma interactions, lead to the induction of metastasis (27). Cancer cells use exosomes as tools to prepare distant sites for metastasis, a phenomenon often referred to as “premetastatic niche” formation. These exosomes can deliver growth factors and other molecules that remodel the microenvironment, making it favorable for metastasis (28). Tumor-derived exosomes usually contain a cell migration-inducing and hyaluronan-binding protein (CEMIP) that can induce pro-inflammatory changes in microglia (M1), later leading to tumor progression in the brain microenvironment (29). Exosomes play crucial roles in transforming the tumor microenvironment, influencing processes such as angiogenesis, immune evasion, and metastasis. In a recent study, exosomes released by tumor cells regulate immune response and disease progression by promoting the M2 macrophage population in the tumor microenvironment (30). Exosomes can mediate the pro-tumorigenic microenvironment by delivering oncogenic signals and promoting the recruitment and activation of various stromal cells (31). Numerous studies further illustrate the capability of exosomes to modify the tumor microenvironment, thereby facilitating metastatic progression. Brain metastatic exosomes disrupt the endothelial tight junction proteins, leading to the compromise of the integrity of the BBB (32, 33). This results in increased permeability, allowing for easier dissemination of metastatic cancer cells. Although exosomes play a profound role in disease development and progression, we can exploit the possibilities of exosomes in therapeutic aspects as well. Exosomes also possess distinct physico-chemical characteristics, as enhanced cellular uptake has a significant impact on theranostic applications. The various implications of exosomes in the disease progression and therapeutic aspects are illustrated in Figure 1 (created using biorender). The schematic illustration describes the multimodal theranostic inference of exosomes in brain cancer disease. Exosomes derived from brain tissues can be used as a leading contender in applications platform, such as drug delivery, prognostic and diagnostic platforms, and disease progression marker identification.
Figure 1
Graphical abstract as an overall conceptualization and review of the literature. Multimodal theranostic implications of exosomes for brain cancer. Exosomes derived from brain tissues can be suitable contenders in applications such as drug delivery, prognostic and diagnostic platforms, and disease progression in the brain cancer regime. The intriguing applications of exosomes range from disease progression markers, such as brain metastasis, tumor microenvironment, epithelial mesenchymal transition, and extracellular matrix (ECM) integrity. However, in therapeutic aspect components, such as machine learning, AI, multi-omics, drug delivery, and other theranostic applications, were covered. The schematic diagram was created using BioRender (https://biorender.com).
4 Theranostic implication of exosome in brain cancer
Glioma is primarily considered a brain tumor. With respect to the cell type of origin, they are sub-classified into ependymomas, astrocytomas, anaplastic astrocytomas, glioblastoma, oligodendrogliomas, and mixed gliomas (34). Among them, Glioblastoma multiforme (GBM) is considered the most aggressive and frequent (60% of total brain tumors) form of malignant tumor in adults (35). Irrespective of advancements in modern therapies, GBM continues to be a deadly disease with a high mortality rate, poor prognosis, and low survival period in the medical field. Although the incidence rate of GBM is comparatively less with respect to other cancer types, GBM stands as the third foremost cause of cancer-related mortality in the age group of 15–34 years (36). The combined insights from studies on exosome-derived mechanisms and their advancements in engineering introduce innovative approaches in glioblastoma management. The therapeutic applications range from targeted delivery to immune modulation, reflecting the dual role of exosomes as both carriers and modulators of treatment strategies (37). Consequently, integrating exosome-based methodologies will open a new paradigm in precision oncology and brain cancer therapy.
Conventional chemotherapy is not adequate to compete GBM due to the complexity and heterogeneity in the pathogenesis (38) of the disease. However, surface-engineered exosomes have been found to be efficient drug delivery cargo due to the presence of an active targeting moiety. Modifications using tumor-penetrating peptides, such as the integrin-specific (iRGD) peptide, enhance the targeting accuracy of exosomes to brain tumors (39). The iRGD (CRGDKGPDC) peptide has been an important targeting moiety in recent years for most solid cancers. The iRGD peptide binds to αv integrins and neuropilin-1 (NRP-1), which is overexpressed in glioblastoma and other brain cancers, significantly enhancing the cellular uptake of therapeutic agents (40). HEK-293T cell-derived exosomes, tailored with iRGD, increase the accumulation of therapeutic agents at tumor sites (41). Such a method not only improves drug delivery efficiency but also helps overcome the challenges of the BBB, which typically hinders the accessibility of conventional drugs (39). An approachable multimodal targeting of iRGD-mediated active targeting of brain cancer cells and the delivery of therapeutic payloads can be achieved by exosomes (Figure 2), which improves the activation and magnitude of caspase-mediated apoptotic cell death and reactive oxygen species accumulation in the targeted brain cancer cells. Moreover, such therapeutics reduce the non-specific off-target effects and preserve healthy brain cells, and by surpassing the BBB, they increase the uptake in the brain tissue.
Figure 2
Multimodal targeting of iRGD-mediated active targeting of brain cancer cells by exosomes. Exosomes isolated from body fluids or cell culture media functionalized with the iRGD peptide as the targeting moiety exhibit enhanced BBB crossing and therapeutic payload delivery in brain cancer cells. Such surface-tailored exosomes release therapeutic payload after vesicular-mediated endocytosis and late lysosomes, leading to burst drug release and mechanistic cell death. The delivery of a therapeutic payload by exosomes improves the activation and magnitude of caspase-mediated apoptotic cell death, and reactive oxygen species accumulation in targeted brain cancer cells can be achieved by iRGD-conjugated exosomes. Also, such therapeutics reduce the non-specific off-target effects and preserve healthy brain cells, and by surpassing the BBB, increase the uptake in the brain tissue. The schematic diagram was created by using BioRender (https://biorender.com).
The combination of drug delivery and diagnostic capabilities in engineered exosomes embodies the concept of theranostics, paving the way for tailored treatment plans based on individual tumor profiles. Understanding these mechanisms is crucial for developing therapeutic strategies that target the intercellular signaling pathways modified by exosomes.
5 Active targeting approach through iRGD-functionalized exosomes
The surface engineering of exosomes with the iRGD peptide provides an active targeted delivery approach by facilitating specific interactions with the overexpressed αv integrins on tumor cell surfaces, thus improving cellular uptake and penetration into the tumors (42). In recent studies, iRGD-functionalized exosomes have been evidenced as a better delivery probe for chemotherapeutics and RNA therapeutics. The specificity of the iRGD peptide to targets αvβ3/ανβ5 integrins and neuropilin receptors, which are frequently expressed in tumor cells, is essential for entering tumor tissues.
iRGD peptide-functionalized exosomes isolated from immature dendritic cells of mice were loaded with Dox and showed an effective therapeutic index in both in vitro and in vivo models (39). Macrophage-generated exosomes are used to load paclitaxel drug and show increased toxicity in drug-resistant MDCKMDR1 (Pgp +) cells (43). Exosomes encapsulated with curcumin, along with a STAT3 inhibitor, resulted in a significant reduction in tumor volume in the mouse tumor model (44). In a combinatorial treatment strategy, multifunctional exosomes functionalized with iRGD loaded with Dox and radioiodine-131(131I) can enhance the efficacy of treatments by facilitating deeper tissue penetration and sustained drug release (41). In a current study, a bifunctional iRGD-functionalized exosome loaded with Dox crosses the BBB and elicits a targeted delivery in a therapeutic intervention of central nervous system lymphoma (39).
Despite the promising capabilities of iRGD-functionalized exosomes as a theranostic delivery system, many challenges remain due to their practical clinical implications. The heterogeneous contents among exosomes, probable immunogenicity, and the lack of standardized production methods limit the iRGD-functionalized exosome from clinical administration (45). Further research is required to improve the capabilities of exosome engineering techniques and optimize the cargo for specific brain cancer types. Combinatorial approaches with existing treatment modalities could also enhance the therapeutic efficacy of these exosome-based systems.
Exosomes hold considerable promise in the treatment of brain cancer (illustrated in Tables 1, 2), and several obstacles must be overcome before their clinical implications can be fully realized. These include the clinical translation, safety and regulatory concerns, manufacturing, and scalability. The lack of extensive, randomized controlled trials (RCTs) is a significant limiting factor for exosome therapeutics in clinical practice. Current clinical studies for diseases, including lung and prostate cancer, are still in their early phases, and more research is required to confirm the applicability, safety, and effectiveness of the treatment. Finding the optimal dose, delivery method, and biomarkers to forecast the response of exosome therapeutics is a key hurdle. Furthermore, the lack of a comprehensive understanding of the long-term effectiveness and off-target effects, which is important for developing uniform treatment procedures (46) Moreover, careful planning of clinical trials to assess both the possible hazards of long-term usage as well as the immediate therapeutic advantages will be necessary to overcome these obstacles (47).
Table 1
| Theranostic aspects | Role/component of exosome | Mechanism of action | Implications of the study | References |
|---|---|---|---|---|
| Diagnostic marker | miR-210, miR-301a | Elevated in serum exosomes; correlates with glioma grade and chemoresistance | Non-invasive grading, prognosis, and prediction | Hamzah et al. (78), Naryzhny et al. (79), Azambuja et al. (80) |
| Drug delivery | Engineered exosomes with chemotherapeutics | Cross BBB and surface modifications (angiopep-2) | Targeted delivery of TMZ, siRNAs, or DNA repair inhibitors in cancer | Yu et al. (59) |
| Drug resistance overcoming | miR-21/TLR8-NF-κB pathway inhibition | Downregulates PTEN and TERF1; blocks exosome-mediated resistance signals | Reverses TMZ resistance in glioma | Yasamineh et al. (81) |
| Immuno-modulation | TNC protein, miR-1246 | T-cell suppression by α5β1/αvβ6 integrins, M2 macrophages polarization | Immunosuppressive microenvironment, immunotherapeutic targets | Bamodu et al. (82) |
| Metastasis monitoring | Exosomal miR-375 | Correlates with brain metastasis in neuroblastoma | Biomarker for metastatic progression and monitoring | Wu et al. (83) |
| Radiotherapy enhancement | Catalase-loaded M1Exosome + anti-PD-L1 | Alleviates hypoxia, inhibits DNA repair, and blocks PD-L1-mediated T-cell suppression | Synergizes with radiotherapy to improve glioma outcomes | Rodrigues et al. (84) |
| Tumor microenvironment remodeling | Astrocyte-derived miR-19a | Transfers miR-19a to tumor cells, suppressing PTEN and myeloid cell recruitment | Promotes metastatic outgrowth; target for microenvironment normalization | Valadi et al. (85) |
Overall summary of multimodal theranostic implications of exosomes for brain cancer.
Brain tissue-derived exosomes have applications in drug delivery, prognostic and diagnostic platforms, disease progression, and biomarker or disease monitoring platforms. This table summarizes the theranostic aspects, roles, or components of exosomes; mechanisms of action of exosomes; and implications of this study.
Table 2
| Main focus | Key findings | Implications in theranostics | References |
|---|---|---|---|
| Exosomes and blood–brain barrier integrity | Exosomes from brain metastatic breast cancer cells disrupt tight junctions and promote metastasis | Promoting brain metastasis and their potential as biomarkers | Lu et al. (26) |
| Immunomodulatory effects of exosomes in glioblastoma | Reviews the roles of exosomes in glioblastomas immunosuppressive microenvironment | Immunotherapy and cancer treatment using targeted exosomes | Benecke et al. (86) |
| Immunoinhibitory proteins in cancer exosomes | Role of tumor-derived exosomes in immune evasion processes | Exosome-based strategies for overcoming immunosuppression in cancers | Whiteside (87) |
| Diagnostic and therapeutic potential of exosomes in brain cancer | Reviews properties that make exosomes suitable for targeted drug delivery in brain tumors | Exosome-based systems to enhance therapeutic precision in brain cancer | Zhang et al. (88) |
| Theranostic properties of exosomes in glioblastoma | Efficacy of exosome-mediated drug delivery in glioblastoma therapies | Exosomes in personalized cancer treatment | Bălașa et al. (89) |
| Clinical applications of exosomes in cancer | Reviews the roles of exosomes in tumor progression, specifically their therapeutic implications | Exosomes as innovative diagnostic and therapeutic tools in clinical practice | Wu et al. (90) |
| Targeting cancer-associated fibroblasts with exosomes | Exosomes can influence fibroblast activity and alter the tumor microenvironment | Exosomes are dual-functional: biomarkers and therapeutic agents | Xue et al. (91) |
| Integrins on tumor-derived exosomes | Integrin profiles that dictate the organotrophic behavior of exosomes | Potential targeting strategies for exosome-mediated therapy | Hoshino et al. (61) |
| Transport of exosomes across the blood–brain barrier | Exosome interactions with the BBB and their implications in CNS diseases, including cancer | Exosomes as delivery vehicles for therapeutics | Banks et al. (92) |
| Recent advances in exosome applications in brain tumor treatment | Reviews the protective role of exosomes in delivering therapeutic content | Improve therapeutic stability and efficacy | Rodrigues et al. (29) |
| Epithelial-mesenchymal transition and exosomes | Exosome contents contribute to EMT and facilitate cancer progression | Exosomes serve as therapeutic targets in cancer therapy | Dhar et al. (93) |
List of reported exosome-mediated applications in theranostic platforms for brain cancer.
Exosomes can be a better nanovehicle for applications such as drug delivery, prognostic and diagnostic platforms, disease progression, and biomarker or disease monitoring platforms. The table summarizes the key focus of the study, the key findings of the reported investigation, and the implications of exosomes in theranostic modalities.
6 Glioblastoma derived exosomes in liquid biopsies and their clinical relevance
In addition to their therapeutic capabilities, exosomes serve as important biomarkers for brain cancer diagnosis. The cargo of exosomes derived from glioblastoma cells, including various nucleic acids and proteins, can reflect the genetic and phenotypic characteristics of the tumor, making them valuable for monitoring disease progression and treatment efficacy (48, 49). In a previous study, RNA content of exosomes, such as miRNAs and mutant p53 correlates with tumor dynamics and patient prognosis, thus assisting in clinical decision-making (50). Additionally, exosomes derived from glioblastoma can influence the tumor microenvironment by modulating immune responses and promoting tumor progression, which indicates their multifaceted roles in glioblastoma pathology (51, 52).
However, due to the intrinsic heterogeneity and small size, exosomes are restricted in their use as liquid biopsies, providing impurities and requiring less efficient separation techniques use as liquid biopsies, providing impurities and requiring less efficient separation techniques (53). Exosomes and the biomarkers they possess, including Deoxyribonucleic acid (DNA), RNA, and proteins, are commonly found in trace amounts in bodily fluids like blood and CSF, challenging to find and may provide false-negative findings (54). It can be difficult to distinguish exosomes originating from tumors from those originating from non-cancerous cells or healthy tissue. Other brain cancers or neurological disorders may also display certain biomarkers, which may lead to unrelated results. Moreover, sensitive detection techniques (such as ddPCR and sophisticated OMICS) are essential for precise quantification of biomarkers from exosomes, which increases the cost of the liquid biopsies (48).
7 Biosensing application of exosomes in diagnostic modalities for glioblastoma
The biomarker potential of exosomes in brain cancer is significant due to their ability to reflect the molecular characteristics of their parent cells. The cargo of exosomes, including proteins and non-coding RNAs, has been studied as a non-invasive diagnostic tool for tracking brain cancer progression and response to therapy (55). A specific exosome-derived miRNA has been shown to correlate with glioma progression, serving as a potential biomarker for disease monitoring (56). The high specificity of biomolecules in the exosome allows the differentiation between primary and metastatic brain tumors, marking their utility in guiding treatment strategies (24). Moreover, the high expression of proteins like CEMIP in exosomes has been linked to cancer prognosis, indicating the diagnostic and prognostic value these vesicles hold (29). The identification and validation of these exosome markers could lead to minimally invasive diagnostic protocols that facilitate timely interventions in brain cancer management.
8 RNAi with exosome as a delivery cargo
Initially, exosomes isolated from human and mouse mast cells contain inherent mRNA and microRNA, which are transported to neighboring cells and function as transportable elements (57). Therapeutically, exosomes demonstrate the capability to deliver specific molecular payloads, such as small interfering RNA (siRNA) and chemotherapeutic agents, directly to target cells. This enhances the therapeutic index and addresses drug resistance observed in many cancer treatments (58).
Exosomes are also employed for the loading of therapeutic cargo, including siRNA and chemotherapeutic agents, and have shown promising results in preclinical models. The synthetic protein nanoparticles designed to mimic exosomes significantly enhanced drug delivery to glioblastoma, illustrating a novel strategy to leverage exosome functionality for therapeutic benefit (59).
9 Exosome in bioinformatics: interpreting complex data
Machine learning and bioinformatics are essential for analyzing the large and intricate data from exosome profiling (60). As a multi-omics molecular reservoir, exosomes serve as a perfect biomolecule for the current library of artificial intelligence (AI) algorithms utilized in pathogenesis and treatment (61). Most studies that employ AI in EVs now focus on creating diagnostic tests; however, in the future, this data may be used to guide logical medication delivery strategies. Important changes in several genes that directly affect EV trafficking, endosomal recycling, and caveolar formation were discovered using phosphoproteomics (62). AI might also help physicians and researchers understand pathophysiology to guide medication administration. AI approaches enable advancement in the research on exosome plasmonic sensing and associated support for diagnostic applications, particularly machine learning algorithms (63). These algorithms are exceptional in flexibility and scalability for managing large datasets, making them crucial for deciphering complicated biosensing data. These AI methods are incorporated into exosome diagnostics and offer crucial methods for choosing and utilizing machine learning algorithms.
Machine learning methods are perfect for evaluating exosome profiles, as they can find trends in large datasets (64). A major advancement in early cancer detection techniques has been made through a machine learning approach for non-invasive cancer diagnosis using exosome protein markers, which achieves high accuracy in identifying cancer types with an advanced biomarker signature and sophisticated data models (65). These algorithms can categorize cancer subtypes, distinguish between carcinogenic and non-cancerous samples, and forecast the results of treatment. Furthermore, bioinformatics is a crucial tool to manage and analyze the vast amounts of data from exosome analysis and extract valuable insights from the intricate molecular profiles of exosomes (66). A paradigm shift in cancer diagnoses has been brought by the combination of liquid biopsies, nanotechnology, machine learning, and bioinformatics. This convergence makes it easier to use exosome analysis for dynamic disease monitoring and non-invasive, accurate early cancer diagnosis. Exosome-based cancer detection has the potential to become a key component of early diagnosis and personalized cancer treatment as these technologies advance, greatly influencing oncology by enhancing patient outcomes and deepening our knowledge of cancer biology.
10 Challenges of exosome therapeutics in brain cancer
Although exosomes possess excellent physico-chemical characteristics as a potential candidate for theranostic cargo in brain cancer diseases, they also come along with some limitations and challenges. This includes scalability, reproducibility, regulatory hurdles, and the heterogeneity of exosomes limits their clinical translation. The lack of reliable separation of exosomes with high yield and purity is one of the biggest challenges in the translatability of exosomes into the clinics. Traditional methods, such as size-exclusion chromatography, density gradient centrifugation, and ultra-centrifugation, are time-consuming, labor-intensive, and frequently co-isolate additional protein or vesicular impurities. These discrepancies hinder scalability and repeatability, which are critical for clinical translation (67). Utilizing exosomes for precise drug delivery applications is extremely difficult due to their complex nature, characterized by their varied molecular components (68). Due to its intrinsic complexity, achieving reliable and efficient drug loading into exosomes is difficult (69, 70). Additionally, exosomes naturally tend to target specific cell types or tissues, and engineered exosomes are challenging to precisely target disease locations (71). Surface-modified exosomes must be identified and bind to the targeted cells while reducing off-target effects to achieve a high degree of accuracy (72). Maintaining this fine balance between selectivity and preventing unforeseen effects is the major obstacle in the preparation of exosome-based drug delivery systems (73). The limited payload capacity of exosomes is another problematic concern for drug delivery systems. Moreover, a scalable manufacturing procedure for exosome synthesis remains a top priority. Production costs may increase significantly due to the difficulty of isolating and purifying exosomes and the requirement for modification for certain therapeutic applications (67). The cost and accessibility of exosome-based therapeutics may be impacted by the expensive nature of exosome manufacturing. The development of more economical and efficient production techniques is required for exosome therapeutics to translate its true potential into the healthcare system.
11 Future direction of exosome in brain cancer
Exosomes are lipid-encased, subcellular (60–80 nm) structures released into the peripheral blood from healthy and diseased cells. Exosome content varies in the physiological and pathological conditions of the same cell type or organ (74). Using exosomes as a diagnostic tool for glioma is considered a less explored area and has high potential with respect to its multitude of accolades. Commonly used biomarkers such as clinical disease activity indices, C-reactive protein (CRP), and fecal calprotectin achieve suboptimal sensitivity and specificity for brain cancer diagnosis. However, an elevated level of CRP indicates poor progression-free and overall survival in PD-1 therapy (75). The imperative need is to identify subtle disease manifestations through precise diagnostic methodologies, which are crucial for assessing disease progression or remission.
Increased sphingomyelin and saturated lipids have also been observed in the lipid profiling of glioblastoma-derived exosomes. Moreover, glioblastoma tissues have been found to contain elevated levels of sphingosine-1-phosphate (S1P), indicating that sphingolipids contribute to tumor invasion, angiogenesis, and metastasis of glioblastoma (76). Extracellular vesicles derived from glioblastoma cells with the IDH1 mutation have been reported to have a difference in lipid profile compared to normal cells (77). Building on this insight, exosomes isolated from peripheral blood referred to as peripheral blood exosomes (PBE), holds a significant potential in diagnosis and improve clinical outcomes due to their distinct lipid compositions. They offer a highly sensitive and non-invasive biomarker platform for accurately assessing disease severity. Continuous follow-up until the achievement of deep remission should be considered the definitive endpoint of therapy, alongside accurate diagnosis of the disease. In this manner, monitoring the brain cancer patients with lipid profiling of PBE, with the intent to suppress clinical cancer progression and significant remission upon therapy, is considered an important aspect in disease management. Moreover, an iRGD peptide-functionalized exosome can enhance its targeting ability by enabling its binding to integrin αvβ3, which is overexpressed in brain cancers. This engineering approach underlines the potential of exosome-based systems in coordinating targeted therapy and overcoming traditional hurdles in cancer treatment.
12 Conclusion
Exosomes, nanoscale extracellular vesicles secreted by cells, serve as carriers for various biomolecules, including proteins, lipids, and nucleic acids, making them valuable for targeted therapy and diagnostics in cancer management. Exosomes are emerging as key players in the progression of brain cancer, influencing both therapeutic approaches and diagnostic strategies. Their role in facilitating metastasis and altering the tumor microenvironment presents both challenges and opportunities for intervention. Advances in exosome engineering provide exciting avenues for enhancing targeted drug delivery systems, potentially transforming therapeutic outcomes (50). Meanwhile, as biomarkers, exosomes offer new hope for improved disease monitoring and personalized treatment strategies (55). Continued research into the multifaceted roles of exosomes will be crucial in shaping future brain cancer therapies. The evaluation of exosome-integrin interactions elucidates the mechanisms through which cancer cells exploit exosomes to their advantage. Integrin expression patterns on exosomes can serve as biomarkers for predicting organotrophic metastasis, underscoring the importance of targeting these pathways in brain-related malignancies (26, 43).
The therapeutic potential of exosomes is expanding with advances in engineering techniques, particularly in enhancing their specificity and uptake in brain tumors. The use of peptides like the iRGD enhances the targeting ability of exosomes by facilitating their binding to integrin αvβ3, which is overexpressed in various tumors (40). The integration of iRGD peptide technology with exosome-based platforms presents a groundbreaking opportunity in brain cancer research and treatment. This multifaceted approach may lead to better-targeted therapies that improve patient outcomes while minimizing systemic toxicity associated with conventional treatments.
The theranostic potential of exosomes in brain cancer is vast, bridging the gap between diagnostic applications and therapeutic strategies. Exosomes not only provide valuable biomarkers for monitoring disease progression but can also be engineered to enhance drug delivery and efficacy in targeting brain tumors. As ongoing research continues to unveil the complexities of exosome biology, their integration into clinical practice could significantly improve outcomes for patients with brain cancer. Future investigations focused on optimizing surface engineering of exosomes, understanding their interactions within the tumor microenvironment, and validating their clinical utility will be integral in translating these findings into meaningful therapies.
Statements
Author contributions
SM: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Methodology, Conceptualization. PD: Data curation, Writing – original draft, Conceptualization, Methodology, Writing – review & editing. BR: Writing – review & editing, Formal analysis, Conceptualization. AJ: Formal analysis, Writing – review & editing. JK: Formal analysis, Project administration, Methodology, Writing – review & editing, Conceptualization, Funding acquisition, Supervision.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
SM thanks Ellis Fischel Cancer Center, University of Missouri, Columbia, for academic and financial support. PD thanks the National Institute of Health, Bethesda, United States, for supporting postdoctoral stipends.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2025.1599392/full#supplementary-material
References
1.
El-Andaloussi S Lee Y Lakhal-Littleton S Li J Seow Y Gardiner C et al . Exosome-mediated delivery of siRNA in vitro and in vivo. Nat Protoc. (2012) 7:2112–26. doi: 10.1038/nprot.2012.131
2.
Mittelbrunn M Gutiérrez-Vázquez C Villarroya-Beltri C González S Sánchez-Cabo F González MÁ et al . Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. (2011) 2:282. doi: 10.1038/ncomms1285
3.
Kanninen KM Bister N Koistinaho J Malm T . Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta Mol basis Dis. (2016) 1862:403–10. doi: 10.1016/j.bbadis.2015.09.020
4.
Greening DW Xu R Ji H Tauro BJ Simpson RJ . A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods bt-proteomic profiling: methods and protocols In: PoschA, editor. New York, NY: Springer New York (2015). 179–209.
5.
Heinemann ML Vykoukal J . Sequential filtration: a gentle method for the isolation of functional extracellular vesicles BT-extracellular vesicles: methods and protocols In: KuoWPJiaS, editors. New York, NY: Springer New York (2017). 33–41.
6.
Théry C Amigorena S Raposo G Clayton A . Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. (2006) 30:Unit 3.22. doi: 10.1002/0471143030.cb0322s30
7.
Davies RT Kim J Jang SC Choi E-J Gho YS Park J . Microfluidic filtration system to isolate extracellular vesicles from blood. Lab Chip. (2012) 12:5202–10. doi: 10.1039/C2LC41006K
8.
Niu Z Pang RTK Liu W Li Q Cheng R Yeung WSB . Polymer-based precipitation preserves biological activities of extracellular vesicles from an endometrial cell line. PLoS One. (2017) 12:e0186534. doi: 10.1371/journal.pone.0186534
9.
Zarovni N Corrado A Guazzi P Zocco D Lari E Radano G et al . Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches. Methods. (2015) 87:46–58. doi: 10.1016/j.ymeth.2015.05.028
10.
Nakase I Kobayashi NB Takatani-Nakase T Yoshida T . Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci Rep. (2015) 5:10300. doi: 10.1038/srep10300
11.
Hood JL . Post isolation modification of exosomes for nanomedicine applications. Nanomedicine. (2016) 11:1745–56. doi: 10.2217/nnm-2016-0102
12.
Haney MJ Klyachko NL Zhao Y Gupta R Plotnikova EG He Z et al . Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. (2015) 207:18–30. doi: 10.1016/j.jconrel.2015.03.033
13.
Pardridge WM . Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. (2012) 32:1959–72. doi: 10.1038/jcbfm.2012.126
14.
Pardridge WM . The Blood-Brain Barrier: Bottleneck in Brain Drug Development. Neuro RX. (2005) 2:3–14. doi: 10.1602/neurorx.2.1.3
15.
Jain KK . Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine. (2012) 7:1225–33. doi: 10.2217/nnm.12.86
16.
Elumalai K Srinivasan S Shanmugam A . Review of the efficacy of nanoparticle-based drug delivery systems for cancer treatment. Biomed. Technol. (2024) 5:109–22. doi: 10.1016/j.bmt.2023.09.001
17.
Syama K Jakubek ZJ Chen S Zaifman J Tam YYC Zou S . Development of lipid nanoparticles and liposomes reference materials (II): cytotoxic profiles. Sci Rep. (2022) 12:18071. doi: 10.1038/s41598-022-23013-2
18.
Juhairiyah F de Lange ECM . Understanding drug delivery to the brain using liposome-based strategies: studies that provide mechanistic insights are essential. AAPS J. (2021) 23:114. doi: 10.1208/s12248-021-00648-z
19.
Morse SV Mishra A Chan TG de Rosales RTM Choi JJ . Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles. J Control Release. (2022) 341:605–15. doi: 10.1016/j.jconrel.2021.12.005
20.
Sharma V Das MC . Exosome as drug delivery system: Current advancements. Extracell Vesicle. (2024) 3:100032. doi: 10.1016/j.vesic.2023.100032
21.
Yang T Martin P Fogarty B Brown A Schurman K Phipps R et al . Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio Rerio. Pharm Res. (2015) 32:2003–14. doi: 10.1007/s11095-014-1593-y
22.
Basak P Badal D Dayal D Bhadada S Kumar R Sachdeva N . Preproinsulin-specific regulatory T cell-derived exosomes loaded with immune-checkpoint ligands can suppress autoimmune responses in type 1 diabetes. Int Immunopharmacol. (2025) 161:115045. doi: 10.1016/j.intimp.2025.115045
23.
Pan B-T Johnstone RM . Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell. (1983) 33:967–78. doi: 10.1016/0092-8674(83)90040-5
24.
Avgoulas DI Tasioulis KS Papi RM Pantazaki AA . Therapeutic and diagnostic potential of exosomes as drug delivery systems in brain cancer. Pharmaceutics. (2023) 15:1439. doi: 10.3390/pharmaceutics15051439
25.
Khatami SH Karami N Taheri-Anganeh M Taghvimi S Tondro G Khorsand M et al . Exosomes: promising delivery tools for overcoming blood-brain barrier and glioblastoma therapy. Mol Neurobiol. (2023) 60:4659–78. doi: 10.1007/s12035-023-03365-0
26.
Lu Y Chen L Li L Cao Y . Exosomes Derived from brain metastatic breast cancer cells destroy the blood-brain barrier by carrying lnc RNA GS1-600G8.5. Biomed Res Int. (2020) 2020:7461727. doi: 10.1155/2020/7461727
27.
Nag S Bhattacharya B Dutta S Mandal D Mukherjee S Anand K et al . Clinical theranostics trademark of exosome in glioblastoma metastasis. ACS Biomater Sci Eng. (2023) 9:5205–21. doi: 10.1021/acsbiomaterials.3c00212
28.
Yang X Zhang Y Zhang Y Zhang S Qiu L Zhuang Z et al . The key role of exosomes on the pre-metastatic niche formation in tumors. Front Mol Biosci. (2021) 8:703640. doi: 10.3389/fmolb.2021.703640
29.
Rodrigues G Hoshino A Kenific CM Matei IR Steiner L Freitas D et al . Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat Cell Biol. (2019) 21:1403–12. doi: 10.1038/s41556-019-0404-4
30.
He Z Wang J Zhu C Xu J Chen P Jiang X et al . Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis. Cancer Lett. (2022) 548:215751. doi: 10.1016/j.canlet.2022.215751
31.
Olejarz W Kubiak-Tomaszewska G Chrzanowska A Lorenc T . Exosomes in angiogenesis and anti-angiogenic therapy in cancers. Int J Mol Sci. (2020) 21:5840. doi: 10.3390/ijms21165840
32.
Tai Y-L Chen K-C Hsieh J-T Shen T-L . Exosomes in cancer development and clinical applications. Cancer Sci. (2018) 109:2364–74. doi: 10.1111/cas.13697
33.
Gan D-X Wang Y-B He M-Y Chen Z-Y Qin X-X Miao Z-W et al . Lung cancer cells-controlled Dkk-1 production in brain metastatic cascade drive microglia to acquire a pro-tumorigenic phenotype. Front Cell Dev Biol. (2020) 8:591405. doi: 10.3389/fcell.2020.591405
34.
Cano-Valdez AM Sevilla-Lizcano DB . “Pathological Classification of Brain Tumors BT-Principles of Neuro-Oncology: Brain & Skull Base.,” In: Monroy-SosaAChakravarthiSSGarza-SalazarJGde laMeneses GarciaAKassamAB, editors. Cham: Springer International Publishing (2021). p. 75–105.
35.
An J Freeman E Stewart IJ Dore M . Association of traumatic brain injury and glioblastoma multiforme: a case series. Mil Med. (2024) 189:e391–5. doi: 10.1093/milmed/usad162
36.
Hanif F Muzaffar K Perveen K Malhi SM Simjee SU . Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. (2017) 18:3–9. doi: 10.22034/APJCP.2017.18.1.3
37.
Essola JM Zhang M Yang H Li F Xia B Mavoungou JF et al . Exosome regulation of immune response mechanism: Pros and cons in immunotherapy. Bioact Mater. (2024) 32:124–46. doi: 10.1016/j.bioactmat.2023.09.018
38.
Pouyan A Ghorbanlo M Eslami M Jahanshahi M Ziaei E Salami A et al . Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies. Mol Cancer. (2025) 24:58. doi: 10.1186/s12943-025-02267-0
39.
Xia T Liu Z Du Y Zhang J Liu X Ouyang J et al . Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma. Biochem Pharmacol. (2024) 223:116138. doi: 10.1016/j.bcp.2024.116138
40.
Kang S Lee S Park S . iRGD peptide as a tumor-penetrating enhancer for tumor-targeted drug delivery. Polymers (Basel). (2020) 12:1906. doi: 10.3390/polym12091906
41.
Wang C Li N Li Y Hou S Zhang W Meng Z et al . Engineering a HEK-293T exosome-based delivery platform for efficient tumor-targeting chemotherapy/internal irradiation combination therapy. J Nanobiotechnol. (2022) 20:247. doi: 10.1186/s12951-022-01462-1
42.
Nikitovic D Kukovyakina E Berdiaki A Tzanakakis A Luss A Vlaskina E et al . Enhancing tumor targeted therapy: the role of iRGD peptide in advanced drug delivery systems. Cancers (Basel). (2024) 16:3768. doi: 10.3390/cancers16223768
43.
You B Xu W Zhang B . Engineering exosomes: a new direction for anticancer treatment. Am J Cancer Res. (2018) 8:1332–42. PMID:
44.
Yan Y Kulsoom SY Li Y Wang Z Xue L Wang F . Advancing cancer therapy: Nanomaterial-based encapsulation strategies for enhanced delivery and efficacy of curcumin. Mater Today Bio. (2025) 33:101963. doi: 10.1016/j.mtbio.2025.101963
45.
Gabaran SG Ghasemzadeh N Rahnama M Karatas E Akbari A Rezaie J . Functionalized exosomes for targeted therapy in cancer and regenerative medicine: genetic, chemical, and physical modifications. Cell Commun Signal. (2025) 23:265. doi: 10.1186/s12964-025-02268-y
46.
Wang C-K Tsai T-H Lee C-H . Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes. Clin Transl Sci. (2024) 17:e13904. doi: 10.1111/cts.13904
47.
Hussen BM Faraj GSH Rasul MF Hidayat HJ Salihi A Baniahmad A et al . Strategies to overcome the main challenges of the use of exosomes as drug carrier for cancer therapy. Cancer Cell Int. (2022) 22:323. doi: 10.1186/s12935-022-02743-3
48.
Yu D Li Y Wang M Gu J Xu W Cai H et al . Exosomes as a new frontier of cancer liquid biopsy. Mol Cancer. (2022) 21:56. doi: 10.1186/s12943-022-01509-9
49.
Yasamineh S Nikben N Hamed Ahmed M Abdul Kareem R Kadhim Al-Aridhy A Hosseini HM . Increasing the sensitivity and accuracy of detecting exosomes as biomarkers for cancer monitoring using optical nanobiosensors. Cancer Cell Int. (2024) 24:189. doi: 10.1186/s12935-024-03379-1
50.
Ghosh S Rajendran RL Mahajan AA Chowdhury A Bera A Guha S et al . Harnessing exosomes as cancer biomarkers in clinical oncology. Cancer Cell Int. (2024) 24:278. doi: 10.1186/s12935-024-03464-5
51.
Di Giulio S Carata E Muci M Mariano S Panzarini E . Impact of hypoxia on the molecular content of glioblastoma-derived exosomes. Extracell Vesicles Circ Nucl Acids. (2024) 5:1–15. doi: 10.20517/evcna.2023.52
52.
De Vrij J Niek Maas SL Kwappenberg KMC Schnoor R Kleijn A Dekker L et al . Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int J Cancer. (2015) 137:1630–42. doi: 10.1002/ijc.29521
53.
Soffietti R Bettegowda C Mellinghoff IK Warren KE Ahluwalia MS De Groot JF et al . Liquid biopsy in gliomas: A RANO review and proposals for clinical applications. Neuro-Oncology. (2022) 24:855–71. doi: 10.1093/neuonc/noac004
54.
Li X Corbett AL Taatizadeh E Tasnim N Little JP Garnis C et al . Challenges and opportunities in exosome research-Perspectives from biology, engineering, and cancer therapy. APL Bioeng. (2019) 3:011503. doi: 10.1063/1.5087122
55.
Kilchert C Wittmann S Vasiljeva L . The regulation and functions of the nuclear RNA exosome complex. Nat Rev Mol Cell Biol. (2016) 17:227–39. doi: 10.1038/nrm.2015.15
56.
Santangelo A Imbrucè P Gardenghi B Belli L Agushi R Tamanini A et al . A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neuro-Oncol. (2018) 136:51–62. doi: 10.1007/s11060-017-2639-x
57.
Mardi N Salahpour-Anarjan F Nemati M Shahsavari Baher N Rahbarghazi R Zarebkohan A . Exosomes; multifaceted nanoplatform for targeting brain cancers. Cancer Lett. (2023) 557:216077. doi: 10.1016/j.canlet.2023.216077
58.
Wang R Liang Q Zhang X Di Z Wang X Di L . Tumor-derived exosomes reversing TMZ resistance by synergistic drug delivery for glioma-targeting treatment. Colloids Surf B Biointerfaces. (2022) 215:112505. doi: 10.1016/j.colsurfb.2022.112505
59.
Wu J-Y Li Y-J Wang J Hu X-B Huang S Luo S et al . Multifunctional exosome-mimetics for targeted anti-glioblastoma therapy by manipulating protein corona. J Nanobiotechnol. (2021) 19:405. doi: 10.1186/s12951-021-01153-3
60.
Chen J Dong H Fu R Liu X Xue F Liu W et al . Machine learning analyses constructed a novel model to predict recurrent thrombosis in adults with essential thrombocythemia. J Thromb Thrombolysis. (2023) 56:291–300. doi: 10.1007/s11239-023-02833-7
61.
Hoshino A Costa-Silva B Shen T-L Rodrigues G Hashimoto A Tesic Mark M et al . Tumour exosome integrins determine organotropic metastasis. Nature. (2015) 527:329–35. doi: 10.1038/nature15756
62.
Michelle HLT Wan AWN Mat ZAA Idris Z Maulidiani M Mat DWNS . Brain Tumours and Inflammatory Markers: Mini-Review. IIUM Med J Malaysia. (2024) 23:19–25. doi: 10.31436/imjm.v23i01.2313
63.
Lin X Zhu J Shen J Zhang Y Zhu J . Advances in exosome plasmonic sensing: Device integration strategies and AI-aided diagnosis. Biosens Bioelectron. (2024) 266:116718. doi: 10.1016/j.bios.2024.116718
64.
Li B Kugeratski FG Kalluri R . A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes. eLife. (2024) 12:RP90390. doi: 10.7554/eLife.90390
65.
Li B Kugeratski FG Kalluri R . A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes. bioRxiv. (2023). doi: 10.1101/2023.07.18.549557
66.
Delshad M Sanaei M-J Mohammadi MH Sadeghi A Bashash D . Exosomal biomarkers: a comprehensive overview of diagnostic and prognostic applications in malignant and non-malignant disorders. Biomol Ther. (2025) 15:587. doi: 10.3390/biom15040587
67.
Sadeghi S Tehrani FR Tahmasebi S Shafiee A Hashemi SM . Exosome engineering in cell therapy and drug delivery. Inflammopharmacology. (2023) 31:145–69. doi: 10.1007/s10787-022-01115-7
68.
McAndrews KM Kalluri R . Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. (2019) 18:52. doi: 10.1186/s12943-019-0963-9
69.
Mathieu M Martin-Jaular L Lavieu G Théry C . Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. (2019) 21:9–17. doi: 10.1038/s41556-018-0250-9
70.
Kalluri R . The biology and function of exosomes in cancer. J Clin Invest. (2016) 126:1208–15. doi: 10.1172/JCI81135
71.
He J Ren W Wang W Han W Jiang L Zhang D et al . Exosomal targeting and its potential clinical application. Drug Deliv Transl Res. (2022) 12:2385–402. doi: 10.1007/s13346-021-01087-1
72.
Sun W Xing C Zhao L Zhao P Yang G Yuan L . Ultrasound Assisted Exosomal Delivery of Tissue Responsive mRNA for Enhanced Efficacy and Minimized Off-Target Effects. Mol Ther Nucleic Acids. (2020) 20:558–67. doi: 10.1016/j.omtn.2020.03.016
73.
Chen H Wang L Zeng X Schwarz H Nanda HS Peng X et al . Exosomes, a New Star for Targeted Delivery. Front Cell Dev Biol. (2021) 9:751079. doi: 10.3389/fcell.2021.751079
74.
Yuana Y Sturk A Nieuwland R . Extracellular vesicles in physiological and pathological conditions. Blood Rev. (2013) 27:31–9. doi: 10.1016/j.blre.2012.12.002
75.
Iivanainen S Ahvonen J Knuuttila A Tiainen S Koivunen JP . Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors. ESMO Open. (2019) 4:e000531. doi: 10.1136/esmoopen-2019-000531
76.
Haraszti RA Didiot M-C Sapp E Leszyk J Shaffer SA Rockwell HE et al . High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J Extracell Vesicles. (2016) 5:32570. doi: 10.3402/jev.v5.32570
77.
Jeong MH Im H Dahl JB . Non-contact microfluidic analysis of the stiffness of single large extracellular vesicles from IDH1-mutated glioblastoma cells. Adv Mater Technol. (2023) 8:2201412. doi: 10.1002/admt.202201412
78.
Lan F Yue X Xia T . Exosomal microRNA-210 is a potentially non-invasive biomarker for the diagnosis and prognosis of glioma. Oncol Lett. (2020) 19:1967–74. doi: 10.3892/ol.2020.11249
79.
Peng J Liang Q Xu Z Cai Y Peng B Li J et al . Current understanding of exosomal micro RNAs in glioma immune regulation and therapeutic responses. Front Immunol. (2021) 12:813747. doi: 10.3389/fimmu.2021.813747
80.
Yang S Sun Y Liu W Zhang Y Sun G Xiang B et al . Exosomes in glioma: unraveling their roles in progression, diagnosis, and therapy. Cancers (Basel). (2024) 16:823. doi: 10.3390/cancers16040823
81.
Chuang H-Y Su Y Liu H-W Chen C-H Chiu S-C Cho D-Y et al . Preclinical evidence of STAT3 inhibitor pacritinib overcoming temozolomide resistance via downregulating miR-21-enriched exosomes from M2 glioblastoma-associated macrophages. J Clin Med. (2019) 8:959. doi: 10.3390/jcm8070959
82.
Qian M Wang S Guo X Wang J Zhang Z Qiu W et al . Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways. Oncogene. (2020) 39:428–42. doi: 10.1038/s41388-019-0996-y
83.
Colletti M Tomao L Galardi A Paolini A Di Paolo V De Stefanis C et al . Neuroblastoma-secreted exosomes carrying miR-375 promote osteogenic differentiation of bone-marrow mesenchymal stromal cells. J Extracell Vesicles. (2020) 9:1774144. doi: 10.1080/20013078.2020.1774144
84.
Ma X Yao M Gao Y Yue Y Li Y Zhang T et al . Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization. Adv Sci (Weinh). (2022) 9:e2106031. doi: 10.1002/advs.202106031
85.
Alečković M Kang Y . Welcoming Treat: Astrocyte-Derived Exosomes Induce PTEN Suppression to Foster Brain Metastasis. Cancer Cell. (2015) 28:554–6. doi: 10.1016/j.ccell.2015.10.010
86.
Benecke L Coray M Umbricht S Chiang D Figueiró F Muller L . Exosomes: small EVs with large immunomodulatory effect in glioblastoma. Int J Mol Sci. (2021) 22:3600. doi: 10.3390/ijms22073600
87.
Whiteside TL . Exosomes carrying immunoinhibitory proteins and their role in cancer. Clin Exp Immunol. (2017) 189:259–67. doi: 10.1111/cei.12974
88.
Zhang M Hu S Liu L Dang P Liu Y Sun Z et al . Engineered exosomes from different sources for cancer-targeted therapy. Signal Transduct Target Ther. (2023) 8:124. doi: 10.1038/s41392-023-01382-y
89.
Bălașa A Șerban G Chinezu R Hurghiș C Tămaș F Manu D . The involvement of exosomes in glioblastoma development, diagnosis, prognosis, and treatment. Brain Sci. (2020) 10:1–16. doi: 10.3390/brainsci10080553
90.
Wu X Wang X Wang J Hao Y Liu F Wang X et al . The Roles of Exosomes as Future Therapeutic Agents and Diagnostic Tools for Glioma. Front Oncol. (2021) 11:733529. doi: 10.3389/fonc.2021.733529
91.
Xue X Wang X Pang M Yu L Qian J Li X et al . An exosomal strategy for targeting cancer-associated fibroblasts mediated tumors desmoplastic microenvironments. J Nanobiotechnol. (2024) 22:196. doi: 10.1186/s12951-024-02452-1
92.
Banks WA Sharma P Bullock KM Hansen KM Ludwig N Whiteside TL . Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation. Int J Mol Sci. (2020) 21:4407. doi: 10.3390/ijms21124407
93.
Dhar R Devi A Gorai S Jha SK Alexiou A Papadakis M . Exosome and epithelial–mesenchymal transition: A complex secret of cancer progression. J Cell Mol Med. (2023) 27:1603–7. doi: 10.1111/jcmm.17755
Summary
Keywords
exosome, brain cancer, theranostic, iRGD-peptide, Blood-Brain Barrier, extracellular vesicles, nanoparticles, liquid biopsy
Citation
Mohiyuddin S, Dipankar P, Robinson B, Jeyabose A and Karthikeyan J (2025) Therapeutic and diagnostic implications of exosomes as natural nanoparticles: a new paradigm in brain cancer disease management. Front. Med. 12:1599392. doi: 10.3389/fmed.2025.1599392
Received
24 March 2025
Accepted
04 June 2025
Published
21 July 2025
Volume
12 - 2025
Edited by
Alice Chen, Consultant, Potomac, MD, United States
Reviewed by
Muthamil Iniyan Appadurai, University of Nebraska Medical Center, United States
Manish Gupta, Veer Bahadur Singh Purvanchal University, India
Updates
Copyright
© 2025 Mohiyuddin, Dipankar, Robinson, Jeyabose and Karthikeyan.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: J. Karthikeyan, karthikeyan.jk@vit.ac.in
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