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The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy.

Liquid biopsy has remarkably facilitated clinical diagnosis and surveillance of cancer via employing a non‐invasive way to detect cancer‐derived components, such as circulating tumor DNA and circulating tumor cells from biological fluid samples. The cancer‐derived exosomes, which are nano‐sized vesicles secreted by cancer cells have been investigated in liquid biopsy as their important roles in intracellular communication and disease development have been revealed. Given the challenges posed by the complicated humoral microenvironment, which contains a variety of different cells and macromolecular substances in addition to the exosomes, it has attracted a large amount of attention to effectively isolate exosomes from collected samples. In this review, the authors aim to analyze classic strategies for separation of cancer‐derived exosomes, giving an extensive discussion of advantages and limitations of these methods. Furthermore, the innovative multi‐strategy methods to realize efficient isolation of cancer‐derived exosomes in practical applications are also presented. Additionally, the possible development trends of exosome separation in to the future is discussed in this review. This paper provides an overview of the latest advances in separation of cancer‐derived exosomes with a discussion of the advantages and limitations of each method. The work highlights the importance of combining microfluidics with multiple separation strategies to develop integrated microsystems for rapid separation of exosomes with high stability and sensitivity, which will ultimately enable a facile and effective operation for early diagnosis and cancer treatment.

Highlights SERPINE1 mediates the transfer of cancer-derived exosomal let-7 g-5p to promote macrophage M2 polarization. Exosomal let-7 g-5p drives M2 polarization by downregulating SOCS7 and relieving its inhibition of STAT3 phosphorylation. SERPINE1 promotes the transcription of let-7 g-5p by activating the JAK2/STAT3 signaling pathway. Background Tumor-associated macrophages (TAMs), particularly M2-polarized TAMs, are significant contributors to tumor progression, immune evasion, and therapy resistance in gastric cancer (GC). Despite efforts to target TAM recruitment or depletion, clinical efficacy remains limited. Consequently, the identification of targets that specifically inhibit or reprogram M2-polarized TAMs presents a promising therapeutic strategy. Objective This study aims to identify a dual-function target in GC cells that drives both malignant phenotypes and M2 macrophage polarization, revealing its molecular mechanisms to provide novel therapeutic targets for selectivly targeting M2-polarized TAMs in GC. Methods Transcriptomic and clinical data from GC and adjacent tissues were utilized to identify mRNAs associated with high M2 macrophage infiltration and poor prognosis. Single-cell sequencing elucidated cell types expressing the target gene. Transwell co-culture and exosome intervention experiments demonstrated its role in M2 polarization. Small RNA sequencing of exosomes, western blotting, and CoIP assays revealed the molecular mechanisms underlying exosome-mediated M2 polarization. Protein array, ChIP and dual-luciferase reporter assays clarified the molecular mechanisms by which the target gene regulated exosomal miRNA. In vivo validation was performed using xenograft tumor models. Results SERPINE1 was identified as a highly expressed mRNA in GC tissues and cells, significantly associated with advanced clinical stages, worse prognosis, and higher M2 macrophage infiltration in patients with GC. SERPINE1 overexpression in GC cells promoted tumor growth and M2 macrophage polarization. SERPINE1 facilitated the transfer of let-7 g-5p to macrophages via cancer-derived exosomes, inducing M2 polarization. Exosomal let-7 g-5p internalized by macrophages downregulated SOCS7 protein levels, disrupting its interaction with STAT3 and relieving the inhibition of STAT3 phosphorylation, thereby leading to STAT3 hyperactivation, which consequently drove M2 polarization. Additionally, in GC cells, elevated SERPINE1 expression activated JAK2, enhancing STAT3 binding to the let-7 g-5p promoter and promoting its transcription, thereby increasing let-7 g-5p levels in exosomes. Conclusion GC cell-derived SERPINE1 , functioning as a primary driver of GC growth and TAM M2 polarization, promotes M2 polarization through the regulation of exosomal let-7 g-5p transfer via autocrine activation of the JAK2/STAT3 signaling pathway. These findings elucidate a novel mechanism of SERPINE1 -induced M2 polarization and highlight SERPINE1 as a promising target for advancing immunotherapy and targeted treatments in GC.

Tumor-derived exosomes are being recognized as essential mediators of intercellular communication between cancer and immune cells. It is well established that bone marrow-derived macrophages (BMDMs) take up tumor-derived exosomes. However, the functional impact of these exosomes on macrophage phenotypes is controversial and not well studied. Here, we show that breast cancer-derived exosomes alter the phenotype of macrophages through the interleukin-6 (IL-6) receptor beta (glycoprotein 130, gp130)-STAT3 signaling pathway. Addition of breast cancer-derived exosomes to macrophages results in the activation of the IL-6 response pathway, including phosphorylation of the key downstream transcription factor STAT3. Exosomal gp130, which is highly enriched in cancer exosomes, triggers the secretion of IL-6 from BMDMs. Moreover, the exposure of BMDMs to cancer-derived exosomes triggers changes from a conventional toward a polarized phenotype often observed in tumor-associated macrophages. All of these effects can be inhibited through the addition of a gp130 inhibitor to cancer-derived exosomes or by blocking BMDMs exosome uptake. Collectively, this work demonstrates that breast cancer-derived exosomes are capable of inducing IL-6 secretion and a pro-survival phenotype in macrophages, partially gp130/STAT3 signaling.

Exosomes belong to the class of extracellular vesicles of endocytic origin, which are regarded as a promising source of cancer biomarkers in liquid biopsy. As a result, an accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affinity-based approaches are recognized as the most valuable technique for exosome isolation and characterization. Indeed, Affibody biomolecules are a type of protein scaffold engineered with small size and enjoy the features of high thermal stability, affinity, and specificity. While the utilization of antibodies, aptamers, and other biologically active substances for exosome detection has been reported widely, there are no reports describing Affibody molecules’ usage for exosome detection. In this study, for the first time, we have proposed a novel strategy of using Affibody functionalized microbeads (AffiBeads) for exosome detection with a high degree of efficiency. As a proof-of-concept, anti-EGFR-AffiBeads were fabricated and applied to capture and detect human lung A549 cancer cell-derived EGFR-positive exosomes using flow cytometry and fluorescent microscopy. Moreover, the capture efficiency of the AffiBeads were compared with its counterpart antibody. Our results showed that the Affibody probe had a detection limit of 15.6 ng exosomes per mL (~12 exosomes per AffiBead). The approach proposed in the current study can be used for sensitive detection of low expression level markers on tumor-derived exosomes, providing a basis for early-stage cancer diagnosis.

Identifying novel breast cancer biomarkers will improve patient stratification, enhance therapeutic outcomes, and help develop non-invasive diagnostics. We compared the proteomic profiles of whole-cell and exosomal samples of representative breast cancer cell subtypes to evaluate the potential of extracellular vesicles as non-invasive disease biomarkers in liquid biopsies. Overall, differentially-expressed proteins in whole-cell and exosome samples (which included markers for invasion, metastasis, angiogenesis, and drug resistance) effectively discriminated subtypes; furthermore, our results confirmed that the proteomic profile of exosomes reflects breast cancer cell-of-origin, which underscores their potential as disease biomarkers. Our study will contribute to identifying biomarkers that support breast cancer patient stratification and developing novel therapeutic strategies. We include an open, interactive web tool to explore the data as a molecular resource that can explain the role of these protein signatures in breast cancer classification. Graphical Abstract ( A ) We quantified proteomic profiles of breast cancer cells (BCCs) and breast cancer-derived exosomes (BCDEs) samples from four breast cancer cell lines representative of common breast cancer subtypes – Her2-positive (Her2, MDA-MB-453), Luminal A (LA, MCF7), Luminal B (LB, ZR-75), and triple-negative (TN, MDA-MB-231). ( B ) We independently performed four comparisons for BCCs and BCDEs, comparing each cell line against the remaining three. ( C ) We identified differentially-expressed proteins (DEPs) for BCCs and BCDEs, defined protein signatures, and functionally analyzed resulting networks. Through pathway inference analysis (PIA), we identified Kyoto Encyclopedia of genes and genomes (KEGG) subpaths and biological Gene Ontology (GO) terms that displayed differential activation. ( D ) We validated our proteomic signature using the Cancer Genome Atlas (TCGA) and the Cancer Proteome Atlas (TCPA) databases, verified that differentially-activated pathways in BCDEs caused a corresponding response in receptor cells, and confirmed that the BCDE proteomic signature reflects their cell-of-origin and identifies candidate disease biomarkers in liquid biopsies

Exosomes, nanoscale extracellular vesicles secreted by various cell types, play pivotal roles in intercellular communication. In cancer, tumor-derived exosomes—referred to as cancer-derived exosomes (CDEs)—have emerged as critical regulators of immune evasion, tumor progression, and therapy resistance within the tumor microenvironment (TME). CDEs modulate immune cell function through the transfer of immunosuppressive proteins, cytokines, and non-coding RNAs, ultimately reprogramming immune surveillance mechanisms. This review provides an in-depth analysis of how CDEs influence major immune cell subsets—including T cells, B cells, NK cells, dendritic cells, macrophages, and myeloid-derived suppressor cells—thereby establishing an immunosuppressive TME. We also explore the potential of immune cell-derived exosomes (IDEs) as emerging immunotherapeutic tools capable of counteracting the suppressive effects of CDEs. Furthermore, we highlight exosome engineering strategies aimed at improving therapeutic cargo delivery, tumor targeting, and antitumor immune activation. Finally, we discuss how exosome profiling offers promise in liquid biopsy diagnostics and how integration with 3D tumor models and advanced bioengineering can accelerate the clinical translation of exosome-based cancer immunotherapies.

Multi-functionalized carbon nanomaterials have attracted interest owing to their excellent synergic properties, such as plasmon resonance energy transfer and surface-enhanced Raman scattering. Particularly, nanoparticle (NP)-decorated graphene (GRP) has been applied in various fields. In this study, silver NP (AgNP)- and magnetic iron oxide NP (IONP)-decorated GRP were prepared and utilized as biosensing platforms. In this case, AgNPs and GRP exhibit plasmonic properties, whereas IONPs exhibit magnetic properties; therefore, this hybrid nanomaterial could function as a magnetoplasmonic substrate for the magnetofluoro-immunosensing (MFI) system. Conversely, exosomes were recently considered high-potential biomarkers for the diagnosis of diseases. However, exosome diagnostic use requires complex isolation and purification methods. Nevertheless, we successfully detected a prostate-cancer-cell-derived exosome (PC-exosome) from non-purified exosomes in a culture media sample using Ag/IO-GRP and dye-tetraspanin antibodies (Ab). First, the anti-prostate-specific antigen was immobilized on the Ag/IO-GRP and it could isolate the PC-exosome from the sample via an external magnetic force. Dye-tetraspanin Ab was added to the sample to induce the sandwich structure. Based on the number of exosomes, the fluorescence intensity from the dye varied and the system exhibited highly sensitive and selective performance. Consequently, these hybrid materials exhibited excellent potential for biosensing platforms.

Cancer stem cells (CSCs) are responsible for therapeutic resistance and recurrence in colorectal cancer. Despite advances in immunotherapy, the inability to specifically eradicate CSCs has led to treatment failure. Hence, identification of appropriate antigen sources is a major challenge in designing dendritic cell (DC)‐based therapeutic strategies against CSCs. Here, in an in vitro model using the HT‐29 colon cancer cell line, we explored the efficacy of DCs loaded with exosomes derived from CSC‐enriched colonospheres (CSCenr‐EXOs) as an antigen source in activating CSC‐specific T‐cell responses. HT‐29 lysate, HT‐29‐EXOs and CSCenr lysate were independently assessed as separate antigen sources. Having confirmed CSCs enrichment in spheroids, CSCenr‐EXOs were purified and characterized, and their impact on DC maturation was investigated. Finally, the impact of the antigen‐pulsed DCs on the proliferation rate and also spheroid destructive capacity of autologous T cells was assessed. CSCenr‐EXOs similar to other antigen groups had no suppressive/negative impacts on phenotypic maturation of DCs as judged by the expression level of costimulatory molecules. Notably, similar to CSCenr lysate, CSCenr‐EXOs significantly increased the IL‐12/IL‐10 ratio in supernatants of mature DCs. CSCenr‐EXO‐loaded DCs effectively promoted T‐cell proliferation. Importantly, T cells stimulated with CSCenr‐EXOs disrupted spheroids' structure. Thus, CSCenr‐EXOs present a novel and promising antigen source that in combination with conventional tumour bulk‐derived antigens should be further explored in pre‐clinical immunotherapeutic settings for the efficacy in hampering recurrence and metastatic spread.

Lung cancer is often diagnosed at an advanced stage and has a poor prognosis. Conventional treatments are not effective for metastatic lung cancer therapy. Although some of molecular targets have been identified with favorable response, those targets cannot be exploited due to the lack of suitable drug carriers. Lung cancer cell-derived exosomes (LCCDEs) receive recent interest in its role in carcinogenesis, diagnosis, therapy, and prognosis of lung cancer due to its biological functions and natural ability to carry donor cell biomolecules. LCCDEs can promote cell proliferation and metastasis, affect angiogenesis, modulate antitumor immune responses during lung cancer carcinogenesis, regulate drug resistance in lung cancer therapy, and be now considered an important component in liquid biopsy assessments for detecting lung cancer. Therapeutic deliverable exosomes are emerging as promising drug delivery agents specifically to tumor high precision medicine because of their natural intercellular communication role, excellent biocompatibility, low immunogenicity, low toxicity, long blood circulation ability, biodegradable characteristics, and their ability to cross various biological barriers. Several studies are currently underway to develop novel diagnostic and prognostic modalities using LCCDEs, and to develop methods of exploiting exosomes for use as efficient drug delivery vehicles. Current status of lung cancer and extensive applicability of LCCDEs are illustrated in this review. The promising data and technologies indicate that the approach on LCCDEs implies the potential application of LCCDEs to clinical management of lung cancer patients.