bims-engexo 2025-09-28 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–09–28
thirteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Wound healing effects of exosomes from hypoxia- and normoxia-expanded adipose-derived stem cells of infant and adult origin.
Metal-polyphenol network-engineered mesenchymal stem cell-derived exosome mimetics mediate inflammatory/immune regulation for enhanced periodontal tissue regeneration.
Exosomal miR-133b-3p modulates TGF-β1/Treg immunomodulation to ameliorate osteoporosis.
Bio fluid exosomes: promises, challenges, and future directions in translational medicine.
Hydrogel Loaded with Aminoethyl Anisamide-Modified Exosomes Attenuates Hepatic Fibrosis by Targeting Activated Hepatic Stellate Cells.
Effectiveness of Exosomes from Different Mesenchymal Stem Cells in the Treatment of Psoriasis: A Murine Study and Meta-Analysis of Experimental Studies.
The Antiangiogenic Effect of VEGF-A siRNA-FAM-Loaded Exosomes.
Exosomes derived from 3D-cultured hUCMSCs exhibit superior hepatoprotection against ALF.
Exosomes from hypoxic pretreated BMSCs attenuate primary Sjögren's syndrome-induced skin injury via PPARγ-mediated M2-like macrophage activation.
Self-Organized Vascularized Hepatic Organoids in Microcapsules for Liver Regeneration.
Navigating the Landscape of Exosomal microRNAs: Charting Their Pivotal Role as Biomarkers in Hematological Malignancies.
Solanum lyratum-Derived Solalyraine A1 Suppresses Non-Small Cell Lung Cancer Through Regulation of Exosome Secretion and Related Protein Biomarkers.
Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy.

Stem Cell Res Ther. 2025 Sep 26. 16(1): 506

Wound healing effects of exosomes from hypoxia- and normoxia-expanded adipose-derived stem cells of infant and adult origin.

Szu-Hsien Wu, Kuang-Kai Hsueh, Yu-Ting Liao, Ming-Te Cheng, Zi-Xuan Tao, Jung-Pan Wang.

   BACKGROUND: Exosomes derived from adipose-derived stem cells (ADSC-Exos) have emerged as promising therapeutic agents for promoting wound healing through paracrine mechanisms. While adult ADSC-Exos have been extensively studied, those derived from infant ADSCs have received limited attention, despite their potentially superior regenerative capacity. In addition, hypoxia preconditioning has been shown to enhance the therapeutic efficacy of stem cells and their secretome; however, its influence on exosome function across different donor ages remains unclear. This study aimed to evaluate and compare the wound healing effects of ADSC-Exos from adult and infant sources expanded under hypoxic and normoxic conditions in a diabetic mouse model.
METHODS: ADSC-Exos were isolated from adult and infant donors cultured under normoxic and hypoxic conditions. Exosomes were characterized by morphology, transmission electron microscopy (TEM) imaging, nanoparticle tracking analysis (NTA), and Western blotting. RNA sequencing was performed to profile miRNAs encapsulated in the exosomes. In vitro assays assessed the effects of exosomes on proliferation, migration, and wound healing in human dermal fibroblasts (HDFs) under high-glucose conditions. In vivo efficacy was evaluated using full-thickness wounds in db/db diabetic mice to assess the therapeutic effects of the exosomes.
RESULTS: Normoxic infant ADSC-Exos exhibited a broader size distribution and a larger mean particle size. Several wound-healing-related miRNAs were upregulated in hypoxic ADSC-Exos from both adult and infant sources. Normoxic infant ADSC-Exos significantly enhanced HDF proliferation and migration, whereas hypoxic adult ADSC-Exos exhibited superior early wound closure. In vivo, normoxic adult ADSC-Exos achieved the fastest wound closure at day 7, and normoxic infant ADSC-Exos showed significantly greater wound closure by day 10. All ADSC-Exos promoted dermal regeneration, with hypoxic adult ADSC-Exos showing the most pronounced effects.
CONCLUSION: Infant ADSC-Exos demonstrated inherent advantages under normoxic conditions, including enhanced effects on cell proliferation, migration and wound regeneration. While hypoxic preconditioning enhanced the efficacy of adult ADSC-Exos, it provided limited additional benefit to infant-derived exosomes, highlighting their intrinsic suitability for regenerative therapies.

Keywords:  Adipose-derived stem cell exosomes (ADSC-Exos); Diabetes; Human dermal fibroblast (HDF); Hypoxia

DOI:  https://doi.org/10.1186/s13287-025-04636-4
Biomaterials. 2025 Sep 18. pii: S0142-9612(25)00615-5. [Epub ahead of print]327 123696

Metal-polyphenol network-engineered mesenchymal stem cell-derived exosome mimetics mediate inflammatory/immune regulation for enhanced periodontal tissue regeneration.

Zhi-Yan Zhou, Zhi-Bang Li, Ni-Shan Shi, Su-Su Feng, Ya-Ru Han, Mei-Tong Liu, Hao Chen, Jian-Hua Li, Shao-Hua Ge, Yang Yu.

  Exosomes represent a promising therapeutic strategy in regenerative medicine; however, challenges such as unscalable production and poor tolerance to pathological host microenvironments impede their clinical translation. To address these limitations, this study developed bone marrow mesenchymal stem cell (BMSC)-derived exosome mimetics (EMs), produced through an optimized extrusion methodology, which enhanced production yield while preserving the core morphology and structure of natural exosomes with augmented functionality in key biological processes. Furthermore, these EMs are coated with a tannic acid (TA)/Fe3+ coordination network that acts as a protective barrier with antioxidative and antibacterial properties. This coating enables EMs to promote stem cell proliferation, migration, osteogenesis, and immunomodulation under inflammatory and oxidative stress conditions. In vivo, the local injection of EM@[TA-Fe3+] effectively suppressed periodontal inflammation and promoted alveolar bone regeneration. These findings advance our understanding of the structural and functional characteristics of EMs and present an efficient strategy for their delivery in bone regeneration especially under inflammatory and/or infectious conditions.

Keywords:  Exosome mimetics; Exosomes; Metal-polyphenol network; Oxidative stress; Tissue regeneration

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123696
Bone. 2025 Sep 23. pii: S8756-3282(25)00270-4. [Epub ahead of print] 117658

Exosomal miR-133b-3p modulates TGF-β1/Treg immunomodulation to ameliorate osteoporosis.

Yun Zhao, Xingyao Yang, Jialun Wang, Fangdong Chen, Guojia Shi, Jun Cheng, Shuxing Xing, Xiao Liu.

   PURPOSE: Osteoporosis (OP) is influenced by dysregulated miRNAs, particularly during osteoblast differentiation. The precise mechanisms are still under debate. This study aimed to explore the impact of bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-133b-3p on the TGF-β1/Treg-mediated immune pathway, offering insights into OP's pathogenesis and potential therapeutic targets.
MATERIALS AND METHODS: Bioinformatics analysis of GEO dataset (GSE64433) identified differentially expressed miRNAs in osteoporosis. Target genes were predicted using TargetScan, miRDB, miRTarBase, and miRWalk databases, followed by GO and KEGG pathway enrichment analyses. An OP rat model was constructed by ovariectomy (n = 36, randomly allocated into three groups: control, OP, and OP+exosomal miR-133b-3p, n = 12 per group). BMSCs were isolated at 12 weeks post-OVX.Flow cytometry was used to identify the surface markers of BMSCs, CD29, CD44, CD106, CD34, and CD45. Exosomes were isolated from passages 3-5 BMSCs using ExoQuick kit. Transmission electron microscopy and nanoparticle tracking analysis were used to observe the morphology and size distribution of exosomes, and the expression of exosomal protein markers CD9, CD63, and TSG101 was detected by Western blot. qRT-PCR was performed to detect miR-133b-3p and TGF-β1 expression in exosomes. Dual-luciferase reporter assay validated the direct interaction between miR-133b-3p and TGF-β1 3'-UTR. Dual-energy X-ray bone densitometry was used to detect bone mineral density (BMD) after 4 weeks of treatment with miR-133b-3p-enriched exosomes (200 μg weekly via tail vein injection). Micro-CT was used to analyze the BV/TV, Tb.N, Tb.Th, SMI, Ct.Th, BA/TA, and Tb.Sp. In vitro experiments using isolated CD4+ T cells were conducted to assess TGF-β1 expression and CD4 + CD25 + Foxp3+ Treg cell differentiation via Western blot, RT-PCR, and flow cytometry. Osteoclast marker enzymes TRAP, MMP-9, and Cathepsin K were identified using immunohistochemistry.
RESULTS: Bioinformatics analysis revealed 27 differentially expressed miRNAs. Target prediction of miR-133b-3p identified 44 high-confidence genes, with TGF-β1 emerging as a key target. BMSCs expressing CD29, CD44, and CD106 (but not CD34 and CD45) were isolated from both control and OP rats. The identified exosomes were roughly spherical with a double-layered membrane, they had a size distribution of about 103.5 ± 8.2 nm and 105.8 ± 10.6 nm, respectively, and had a positive expression of CD9 CD63, and TSG101. qRT-PCR analysis revealed significantly decreased miR-133b-3p expression in OP group exosomes (P < 0.001). Dual-luciferase assay confirmed direct binding of miR-133b-3p to TGF-β1 3'-UTR. Treating OP rats with exosomal miR-133b-3p improved various bone metrics, increased BV/TV, Tb.N, Tb.Th, BMD, Ct.Th, and BA/TA, decreased Tb.Sp and SMI, and improved bone histopathological changes in rat bone tissue. It decreased osteoclast marker enzyme TRAP, MMP-9, and Cathepsin K expression (P < 0.001). In vitro experiments demonstrated that miR-133b-3p-enriched exosomes promoted TGF-β1 expression and CD4 + CD25 + Foxp3+ Treg cell differentiation, while miR-133b-3p inhibitor exosomes had opposite effects.
CONCLUSION: Exosomal miR-133b-3p derived from BMSCs mitigates OP in rats, acting via the TGF-β1/Treg-mediated immune pathway, presenting a promising avenue for OP therapy.

Keywords:  Bone marrow mesenchymal stem cells; Immunomodulation; Osteoporosis; TGF-β1/Treg; miR-133b-3p

DOI:  https://doi.org/10.1016/j.bone.2025.117658
J Transl Med. 2025 Sep 23. 23(1): 993

Bio fluid exosomes: promises, challenges, and future directions in translational medicine.

Fatemeh Soltanmohammadi, Maryam Maghsoodi, Effat Alizadeh, Khosro Adibkia, Yadollah Azarmi, Adel Mahmoudi Gharehbaba, Yousef Javadzadeh.

  Exosomes, a subset of extracellular vesicles (EVs) secreted by virtually all cell types, have emerged as pivotal nanocarriers of bioactive molecules, including proteins, nucleic acids, and lipids, facilitating intercellular communication and modulating physiological and pathological processes. Initially discovered in reticulocytes, exosomes have since been recognized for their diverse roles in immune regulation, antigen presentation, and disease progression, paving the way for their application in diagnostics, therapeutics, and personalized medicine. This review comprehensively examines biofluid-derived exosomes, focusing on their biogenesis, molecular composition, and innovative isolation techniques from various biological fluids. We highlight their diagnostic potential as non-invasive biomarkers for diseases such as cancer, neurodegenerative disorders, and infectious diseases, as well as their therapeutic applications in drug delivery, regenerative medicine, and immunotherapy. Additionally, we discuss ongoing and completed clinical trials leveraging exosomes for precision medicine, while addressing the technical challenges and limitations in exosome isolation, characterization, and clinical translation. By integrating the latest advancements and future perspectives, this review underscores the transformative potential of biofluid exosomes in revolutionizing modern medicine.

Keywords:  Biofluids; Diagnosis; Drug delivery; Exosome; Treatment

DOI:  https://doi.org/10.1186/s12967-025-06886-5
ACS Nano. 2025 Sep 23.

Hydrogel Loaded with Aminoethyl Anisamide-Modified Exosomes Attenuates Hepatic Fibrosis by Targeting Activated Hepatic Stellate Cells.

Zongbin Sun, Qiuxia Zheng, Yue Zhang, Chongyang Bai, Fanghong Wang, Ping Yang, Dan Zhu, Xiaoyuan Liu, Shang Li, Desheng Liu, Rui Li, Liu He, Jia Yao, Xun Li.

  Stem cell-based regenerative research has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) for hepatic tissue regeneration and repair. However, exosomes undergo rapid clearance following systemic administration, limiting their therapeutic potential because of insufficient retention and sustained release. In this study, an innovative hydrogel-mediated delivery platform encapsulating aminoethyl anisamide (AEAA)-functionalized exosomes was developed to mitigate hepatic fibrosis. By synthesizing a hydrogel (CMC-OD/TA-Fe(III), Gel) composed of carboxymethyl chitosan, oxidized dextran, and iron tannate, and then encapsulating umbilical cord mesenchymal stem cell-derived exosomes functionalized by AEAA (AEAA-Exos), we implanted this Gel/AEAA-Exos into mice with hepatic fibrosis by intraperitoneal injection to evaluate the therapeutic effect of the hydrogel. The hydrogel had favorable physical properties, optimal biocompatibility, and a sustained-release profile. And Gel/AEAA-Exos system significantly reduced oxidative stress and alleviated hepatic fibrosis. Additionally, RNA-seq revealed that the Gel/AEAA-Exos system ameliorates hepatic fibrogenesis mainly by modulating oxidative stress, collagen deposition, and inflammatory cascade in liver tissues. This strategy offers a targeted and efficient approach for treating liver fibrosis induced by chronic hepatic injury and improves targeting efficiency and therapeutic outcomes through engineered exosome delivery.

Keywords:  AEAA-engineered exosomes; antihepatic fibrosis; hydrogel; sustained release; target

DOI:  https://doi.org/10.1021/acsnano.5c06003
Biomedicines. 2025 Aug 28. pii: 2093. [Epub ahead of print]13(9):

Effectiveness of Exosomes from Different Mesenchymal Stem Cells in the Treatment of Psoriasis: A Murine Study and Meta-Analysis of Experimental Studies.

Yu-Chen Huang, Chao-Yuan Chang, Chun-Jen Huang.

  Background/Objectives: Psoriasis is a chronic systemic inflammatory disease. Evidence on the efficacy of different mesenchymal stem cell (MSC) exosomes for psoriasis remains limited. This study aimed to evaluate the therapeutic effects of different MSC exosomes in mitigating psoriasis. Methods: The efficacy of human placenta MSC (hPMSC) and human umbilical cord MSC (hUCMSC) exosomes was compared in an imiquimod (IMQ)-induced psoriasis murine model. A meta-analysis was performed to incorporate the results of studies using IMQ-induced psoriasis murine models to compare MSC exosome treatments (exosome group) with vehicle or no-treatment controls (control group). Results: In this murine study, both the hPMSC and hUCMSC exosomes showed better effectiveness in reducing epidermal thickness and skin tissue cytokines than controls, but no significant difference was observed between the two MSC exosomes. Seven studies were included in the meta-analysis. Clinical severity scores were significantly lower in the exosome group than in the controls (standardized mean difference [SMD]: -1.886; 95% confidence interval [CI]: -3.047 to -0.724). Epidermal thickness was significantly reduced (SMD: -3.258; 95% CI: -4.987 to -1.529). No significant differences were found in most skin cytokines between the groups, although tumor necrosis factor-α mRNA (SMD: -0.880; 95% CI: -1.623 to -0.136) and interleukin-17A protein levels (SMD: -2.390; 95% CI: -4.522 to -0.258) were both lower in the exosome group. Meta-regression revealed a greater improvement in clinical scores in studies using hUCMSC exosomes compared to other MSC sources (p = 0.030). Conclusions: hUCMSC exosomes have been studied more extensively than other MSC exosomes. MSC exosomes reduce clinical severity and epidermal hyperplasia.

Keywords:  exosomes; extracellular vesicles; mesenchymal stem cells; meta-analysis; psoriasis; systematic review

DOI:  https://doi.org/10.3390/biomedicines13092093
Bioengineering (Basel). 2025 Aug 26. pii: 919. [Epub ahead of print]12(9):

The Antiangiogenic Effect of VEGF-A siRNA-FAM-Loaded Exosomes.

Woojune Hur, Basanta Bhujel, Seheon Oh, Seorin Lee, Ho Seok Chung, Jin Hyoung Park, Jae Yong Kim.

  Neovascular ocular diseases are caused by vascular endothelial growth factor A (VEGFA) overexpression. Thus, VEGFA inhibition is considered the main strategy for treating ocular neovascularization. However, existing anti-VEGF therapies have several limitations in stability and delivery efficiency. To overcome the limitations, exosome-based VEGF siRNA delivery technology has attracted attention since exosomes have the advantages of high in vivo stability and excellent intracellular delivery efficiency. Additionally, loading VEGFA siRNA into exosomes not only allows for targeting specific cells or tissues but can also improve therapeutic efficacy. Our research team purified and concentrated exosomes using chromatography techniques, added fluorescein amidite (FAM)-labeled VEGFA siRNA into exosomes, and observed the novel effect of drug delivery in vitro. This study successfully introduced hVEGFA siRNA-FAM into target cells, with high efficacy particularly at 48 h after treatment. Furthermore, the enhanced inhibition of VEGFA expression at 48 h post-treatment was confirmed. FACS analysis was performed using the apoptosis markers Annexin V-FITC (green) and PI-PE (red) to confirm the presence or absence of apoptosis. Both groups treated with hVEGFA siRNA-FAM-EXO (1) and hVEGFA siRNA-FAM-EXO (2) showed increased apoptosis as the exposure time passed compared to the untreated group (0 h). hVEGFA siRNA-FAM-EXO treatment effectively induced apoptosis. After 24 h, early apoptosis was 12.9% and 13.9% and late apoptosis was 1.5% and 3.7% in hVEGFA siRNA-FAM-EXO groups (1) and (2), respectively. After 48 h, early apoptosis was 23.9% and late apoptosis was 39.4% and 17.8% in hVEGFA siRNA-FAM-EXO groups (1) and (2), respectively, indicating a time-dependent pattern of apoptosis progression. Additionally, tube formation of human vascular endothelial cells (HUVECs) was induced to confirm the effect of VEGFA siRNA-loaded exosomes on the angiogenesis assay in vitro. Compared with controls, angiogenesis became significantly weakened in hVEGFA siRNA-FAM-EXO (1)- and hVEGFA siRNA-FAM-EXO (2)-treated groups at 48 h post-treatment and completely disappeared at 72 h, probably occurring due to decreased VEGFA, PIGF, and VEGFC in the intracellular cytosol and conditioned media secreted by VEGFA siRNA-FAM in HUVECs. In conclusions, FAM-tagged VEGFA siRNA was packed into exosomes and degraded over time after tube formation, leading to cell death due to a decrease in VEGFA, PIGF, and VEGFC levels. This study is expected to support the development of in vivo neovascularization models (keratitis, conjunctivitis, or diabetic retinopathy models) in the future.

Keywords:  VEGFA siRNA-loaded exosomes; apoptosis; exosomes; neovascularization; tube formation

DOI:  https://doi.org/10.3390/bioengineering12090919
iScience. 2025 Sep 19. 28(9): 113419

Exosomes derived from 3D-cultured hUCMSCs exhibit superior hepatoprotection against ALF.

Huixin Tang, Wang Lu, Qi Yang, Yizhi Zhang, Xiaoxuan Liu, Shanshan Li, Manman Xu, Zhongping Duan, Li Bai, Yu Chen.

  Most recently, exosomes (Exos) derived from 3D-cultured cells exhibit great advantages over 2D-Exos. Nevertheless, it remains to be explored whether 3D (tissue engineering liver) exosomes are superior to 2D-Exos in protecting mice from acute liver injury (ALF) and the underlying mechanism. Herein, we demonstrated that 3D-Exos manifested higher yields, protein concentration and RNA content compared to 2D-Exos. Remarkably, 3D-Exos exhibited superior hepatoprotection against ALF, as shown by reduced TBiL levels, improved liver architecture and alleviated inflammation. According to miRNA sequencing and KEGG enrichment analysis, the differentially expressed genes between 2D- and 3D-Exos could be enriched in "Hippo-YAP" and "autophagy" pathways. Moreover, the levels of YAP/TAZ and autophagy markers were more elevated in 3D-Exos-treated mice. Specifically, inhibiting YAP and autophagy signaling destroyed the hepatoprotection conferred by 3D-Exos. Collectively, 3D-Exos exert superior hepatoprotection against ALF by up-regulating YAP and autophagy signaling. Our finding provides powerful support for administering 3D-Exos to treat ALF efficiently.

Keywords:  Biochemistry; Cell biology; Tissue Engineering

DOI:  https://doi.org/10.1016/j.isci.2025.113419
Cell Immunol. 2025 Sep 03. pii: S0008-8749(25)00109-1. [Epub ahead of print]418 105023

Exosomes from hypoxic pretreated BMSCs attenuate primary Sjögren's syndrome-induced skin injury via PPARγ-mediated M2-like macrophage activation.

Xin Wang, Xu Sun, Xinmeng Yang, Guixia Xu, Yuan Wang, Mingming Jin, Chao Sun.

   BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disorder identified by a triad of sicca symptoms, pain, and fatigue. SS-induced skin injury seriously affects people's health but remains unsolved. Accumulating investigations have confirmed that exosomes (Exos) originating from bone marrow mesenchymal stem cells (BMSCs) can bolster the stressed microenvironment and tissue repair. Present study aimed to unravel therapeutic effects regarding BMSC Exos on SS-induced skin injury.
METHODS: In this study, an SS mouse model was constructed, and exosomes from BMSCs (Exos) and hypoxic pretreated BMSCs (HExos) were isolated. The therapeutic effects of exosomes in SS were identified using ELISA, immunohistochemistry, and immunofluorescence. High-throughput sequencing (HTS) was utilized to characterize differentially expressed genes between Exos and HExos.
RESULTS: The data showed that Exos, especially HExo treatments, affected the inhibition of SS-induced inflammatory factor expression, cell apoptosis, ROS deposition, and collagen loss. HTS and RT-qPCR detection showed PPARγ functioned importantly for HExo-mediated protective effects against SS-induced skin injury. The in vitro experiment using RAW confirmed that PPARγ expression inhibited LPS-induced M1-like macrophage activation, which was confirmed using the PPARγ antagonist T0070907. PPARγ upregulation improved therapeutic effects regarding Exos upon skin injury in SS mice by promoting M2-like macrophage activation.
CONCLUSION: Taken together, our study found that exosomes from hypoxic pretreated BMSCs attenuated primary Sjögren's syndrome-induced skin injury via PPARγ delivery and promoted M2-like macrophage activation.

Keywords:  Bone marrow mesenchymal stem cells; Exosomes; M2 macrophage; PPARγ; Sjögren's syndrome

DOI:  https://doi.org/10.1016/j.cellimm.2025.105023
Research (Wash D C). 2025 ;8 0898

Self-Organized Vascularized Hepatic Organoids in Microcapsules for Liver Regeneration.

Yue Zhi, Jinglin Wang, Danqing Huang, Yuanjin Zhao.

Hepatic organoids represent a promising strategy for liver regeneration; however, challenges remain in flexibly tailoring them to achieve complex architectures and vascularized structures for enhanced functionality. Here, we propose a novel system of self-organized vascularized hepatic organoids (SOVHOs) encapsulated in hydrogel microcapsules with biomimetic features for liver regeneration. The hydrogel shell microcapsules encapsulating human umbilical vein endothelial cells and hepatic organoids derived from human induced pluripotent stem cells were generated using microfluidic encapsulation technology. The hydrogel shell provides a 3-dimensional culture environment that supports the formation of uniform hepatocyte spheroids with vascular networks inside the microcapsules. The SOVHOs exhibit liver-specific functions, including drug metabolism, urea synthesis, and serum protein production. In rats with acute liver failure, we demonstrated that the SOVHOs markedly enhanced survival rate and normalize the inflammatory response after transplantation, indicating their remarkable repopulation capacity in facilitating injured liver recovery. Furthermore, SOVHOs remained viable in the host liver for at least 7 days post-implantation, exhibiting low immunogenicity and no detectable adverse effects in rats during this period. These results suggest that our SOVHOs are potentially valuable for clinical application in liver disease treatment.

DOI: https://doi.org/10.34133/research.0898
Noncoding RNA. 2025 Aug 31. pii: 64. [Epub ahead of print]11(5):

Navigating the Landscape of Exosomal microRNAs: Charting Their Pivotal Role as Biomarkers in Hematological Malignancies.

Manlio Fazio, Fabio Stagno, Giuseppa Penna, Giuseppe Mirabile, Alessandro Allegra.

  Under physiological and pathological conditions, all cells release extracellular vesicles named exosomes, which act as transporters of lipidic, protein, and genetic material from parent to recipient cells. Neoplastic cells can secrete higher number of exosomes to exert pro-tumoral effects such as microenvironmental changes, disease progression, immunosuppression and drug-resistance. This holds true for both organ-specific cancers and hematologic malignancies. One of the most important components of exosomal cargo are microRNAs which can mediate all the abovementioned effects. More specifically, microRNAs are small non-coding RNAs, routinely detected through quantitative real-time PCR, which act as translational suppressors by regulating protein-coding genes. Considering their high stability in all body fluids and viability in circulation, research is currently focusing on this type of RNAs for the so called "liquid biopsy", a non-invasive tool for disease diagnosis and longitudinal monitoring. However, several issues remain to be solved including the lack of standardized protocols for exosome isolation and miRNA detection. Starting with this premise, our review aims to provide a wide description of the known microRNA panels employed in the prominent hematological malignancies, which will hopefully redefine the approach to these very challenging diseases in the near future.

Keywords:  biomarkers; extracellular vesicles; hematological malignancies; intercellular communication; liquid biopsy; microRNA; microenvironment; target therapy; tumor-derived exosomes

DOI:  https://doi.org/10.3390/ncrna11050064
Pharmaceuticals (Basel). 2025 Aug 27. pii: 1280. [Epub ahead of print]18(9):

Solanum lyratum-Derived Solalyraine A1 Suppresses Non-Small Cell Lung Cancer Through Regulation of Exosome Secretion and Related Protein Biomarkers.

Pu Jiang, Liangyu Liu, Lixian Chen, Bing Han, Xiao Du.

  Background: Lung cancer is a prevalent malignancy globally, with non-small cell lung cancer (NSCLC) accounting for 80-85% of cases. Solalyraine A1 (SA1) is a steroidal glycoalkaloid derived from Solanum lyratum. However, the effect and mechanism of SA1 on NSCLC remain unclear. Methods: The exosomes from SA1-treated A549 cells were prepared and administered to A549 xenograft mice. Proteomics analysis of SA1-treated A549 cells and their exosomes was conducted to assess the mechanism. Bioinformatics analysis was utilized to identify differentially expressed proteins (DEPs) and key signaling pathways. Western blot analysis confirmed the expression of potential targets. Results: SA1 effectively suppressed tumor growth in A549 xenografts, demonstrating a remarkable inhibition rate of 70.48%. A total of 1154 DEPs were identified in A549 cells, primarily associated with the ribosome pathway. Additionally, 746 DEPs were identified in exosomes, mainly involved in the spliceosome pathway. Five highly regulated DEPs were selected for verification. SA1 was found to suppress MUC5B and elevate APOB expression in A549 cells, while inhibiting MFGM, ANGL4 and increasing GCN1 expression in exosomes. Conclusions: This study demonstrates that SA1 exhibits anti-NSCLC effects by regulating exosome function and related protein expression, providing novel insights for NSCLC treatment.

Keywords:  NSCLC; Solanum lyratum; exosome; proteomics; solalyraine A1; steroidal glycoalkaloid

DOI:  https://doi.org/10.3390/ph18091280
bioRxiv. 2025 Sep 17. pii: 2025.09.12.675975. [Epub ahead of print]

Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy.

Xiao Lei Chen, Kevin M Tharp, Marjaana Ojalill, Duygu Ozmadenci, Antonia Boyer, Terrance J Hannen, Christine Lawson, Hyojae James Lee, Marvin Xia, Elise Tahon, Yichi Zhang, Cray Minor, Safir Ullah Khan, Colin C Anderson, Travis Nemkov, Michael Rose, Monica V Estrada, Alfredo A Molinolo, Elias Warren, Patrick Penolosa, Ramez N Eskander, Michael T McHale, Shizhen E Wang, Denise C Connolly, Kathleen M Fisch, Dwayne G Stupack, David D Schlaepfer.

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition.
eTOC Blurb: High-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation.
Bullet points: Genetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltrationTumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13FAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structuresOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13.

DOI: https://doi.org/10.1101/2025.09.12.675975