bims-engexo 2024-06-23 papers

bims-engexo

Biomed News

on Engineered Exosomes

Issue of 2024‒06‒23
sixteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Harnessing exosomes and plant-derived exosomes as nanocarriers for the efficient delivery of plant bioactives.
BMSC‑derived exosome‑mediated miR‑25‑3p delivery protects against myocardial ischemia/reperfusion injury by constraining M1‑like macrophage polarization.
Frontiers of Plant-derived Exosomes from Research Methods to Pharmaceutical Applications in Plant-based Therapeutics.
The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy.
Standardized Reporting of Research on Exosomes to Ensure Rigor and Reproducibility.
Characterization of exosome-mediated propagation of systemic inflammatory responses into the Central Nervous System.
Therapeutic potential of mesenchymal stem cell-derived exosomes in skeletal diseases.
CAR-T cell-derived exosomes: a new perspective for cancer therapy.
Exosomes as drug delivery systems in glioma immunotherapy.
Salivary exosomal microRNA profile as biomonitoring tool for diagnosis and prognosis of patients with head and neck squamous cell carcinoma: a systematic review.
Exosomes derived from colorectal cancer cells take part in activation of stromal fibroblasts through regulating PHLPP isoforms.
Analysis of MicroRNA Cargo in Circulating Extracellular Vesicles from HIV-Infected Individuals with Pulmonary Hypertension.
Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.
Advances in engineered nanosystems: immunomodulatory interactions for therapeutic applications.
Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer.
Molecular insights to therapeutic in cancer: role of exosomes in tumor microenvironment, metastatic progression and drug resistance.

Nanomedicine (Lond). 2024 Jun 20. 1-19

Harnessing exosomes and plant-derived exosomes as nanocarriers for the efficient delivery of plant bioactives.

Pooja Kathait, Pradeep Kumar Patel, Alakh N Sahu.

  Exosomes, a category of extracellular vesicle (EV), are phospholipid bilayer structures ranging from 30 to 150 nm, produced by various organisms through the endosomal pathway. Recent studies have established the utilization of exosomes as nanocarriers for drug distribution across various therapeutic areas including cancer, acute liver injury, neuroprotection, oxidative stress, inflammation, etc. The importance of plant-derived exosomes and exosome vesicles derived from mammalian cells or milk, loaded with potent plant bioactives for various therapeutic indications are discussed along with insights into future perspectives. Moreover, this review provides a detailed understanding of exosome biogenesis, their composition, classification, stability of different types of exosomes, and different routes of administration along with the standard techniques used for isolating, purifying, and characterizing exosomes.

Keywords:  animal-derived exosomes; exosomes; extracellular vesicles; formulation; nanomedicine; plant bioactives; plant extract; plant-derived exosomes

DOI:  https://doi.org/10.1080/17435889.2024.2354159
Mol Med Rep. 2024 Aug;pii: 142. [Epub ahead of print]30(2):

BMSC‑derived exosome‑mediated miR‑25‑3p delivery protects against myocardial ischemia/reperfusion injury by constraining M1‑like macrophage polarization.

Jingxia Du, Yibo Dong, Jingjing Song, Hanqi Shui, Chengyao Xiao, Yue Hu, Shiyao Zhou, Shanshan Wang.

  Myocardial ischemia/reperfusion injury (MIRI) is a significant challenge in the management of myocardial ischemic disease. Extensive evidence suggests that the macrophage‑mediated inflammatory response may play a vital role in MIRI. Mesenchymal stem cells and, in particular, exosomes derived from these cells, may be key mediators of myocardial injury and repair. However, whether exosomes protect the heart by regulating the polarization of macrophages and the exact mechanisms involved are poorly understood. The present study aimed to determine whether exosomes secreted by bone marrow mesenchymal stem cells (BMSC‑Exo) harboring miR‑25‑3p can alter the phenotype of macrophages by affecting the JAK2/STAT3 signaling pathway, which reduces the inflammatory response and protects against MIRI. An in vivo MIRI model was established in rats by ligating the anterior descending region of the left coronary artery for 30 min followed by reperfusion for 120 min, and BMSC‑Exo carrying miR‑25‑3p (BMSC‑Exo‑25‑3p) were administered through tail vein injection. A hypoxia‑reoxygenation model of H9C2 cells was established, and the cells were cocultured with BMSC‑Exo‑25‑3p in vitro. The results of the present study demonstrated that BMSC‑Exo or BMSC‑Exo‑25‑3p could be taken up by cardiomyocytes in vivo and H9C2 cells in vitro. BMSC‑Exo‑25‑3p demonstrated powerful cardioprotective effects by decreasing the cardiac infarct size, reducing the incidence of malignant arrhythmias and attenuating myocardial enzyme activity, as indicated by lactate dehydrogenase and creatine kinase levels. It induced M1‑like macrophage polarization after myocardial ischemia/reperfusion (I/R), as evidenced by the increase in iNOS expression through immunofluorescence staining and upregulation of proinflammatory cytokines through RT‑qPCR, such as interleukin‑1β (IL‑1β) and interleukin‑6 (IL‑6). As hypothesized, BMSC‑Exo‑25‑3p inhibited M1‑like macrophage polarization and proinflammatory cytokine expression while promoting M2‑like macrophage polarization. Mechanistically, the JAK2/STAT3 signaling pathway was activated after I/R in vivo and in LPS‑stimulated macrophages in vitro, and BMSC‑Exo‑25‑3p pretreatment inhibited this activation. The results of the present study indicate that the attenuation of MIRI by BMSC‑Exo‑25‑3p may be related to JAK2/STAT3 signaling pathway inactivation and subsequent inhibition of M1‑like macrophage polarization.

Keywords:  JAK2; STAT3; exosome; ischemia/reperfusion; macrophage polarization; miR‑25‑3p

DOI:  https://doi.org/10.3892/mmr.2024.13266
Curr Drug Deliv. 2024 Jun 11.

Frontiers of Plant-derived Exosomes from Research Methods to Pharmaceutical Applications in Plant-based Therapeutics.

Wenshang Fu, Pingli Zhang, Wei Wang, Mengdie Du, Rui Ni, Yongshun Sun.

  Exosomes have emerged as critical mediators of intercellular communication and various physiological processes between cells and their environment. These nano-sized vesicles have been extensively investigated and confirmed to exhibit multifunctionality in animal systems. In particular, they participate in intercellular signaling, influence disease progression, and exhibit biological activity. However, Plant-Derived Exosomes (PDEs), especially therapeutic PDEs, have received relatively limited attention in the past few decades. Recent studies have demonstrated that PDEs are involved in signaling molecule transport in addition to intercellular communication, as they serve as functional molecules in the cellular microenvironment. This characteristic highlights the immense potential of PDEs for a wide array of applications, including antioxidation, anti-inflammation, tumour cell elimination, immune modulation, and tissue regeneration. In addition, PDEs hold substantial promise as efficient drug carriers, enhancing the stability and bioavailability of therapeutic agents and consequently enabling targeted delivery to specific cells or tissues. Therefore, PDEs may serve as effective tools for drug delivery and the treatment of various diseases. This comprehensive review provides an overview of recent studies on therapeutic PDEs, focusing on their extraction, isolation, characterization methods, biological activities, and application prospects. It summarises the research progress of exosome-like nanovesicles derived from medicinal plants, with a specific emphasis on traditional Chinese medicine, and highlights their importance in disease treatment and nanoparticle delivery. The main objective is to accelerate the clinical translation of these nanovesicles while providing novel approaches and methodologies for the research and development of innovative drugs.

Keywords:  Exosomes; drug carrier.; extraction and purification methods; identification methods; mechanisms of action; plants

DOI:  https://doi.org/10.2174/0115672018305953240606063911
Circ Res. 2024 Jun 21. 135(1): 198-221

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy.

Alin Rai, Bethany Claridge, Jonathan Lozano, David W Greening.

  From their humble discovery as cellular debris to cementing their natural capacity to transfer functional molecules between cells, the long-winded journey of extracellular vesicles (EVs) now stands at the precipice as a next-generation cell-free therapeutic tool to revolutionize modern-day medicine. This perspective provides a snapshot of the discovery of EVs to their emergence as a vibrant field of biology and the renaissance they usher in the field of biomedical sciences as therapeutic agents for cardiovascular pathologies. Rapid development of bioengineered EVs is providing innovative opportunities to overcome biological challenges of natural EVs such as potency, cargo loading and enhanced secretion, targeting and circulation half-life, localized and sustained delivery strategies, approaches to enhance systemic circulation, uptake and lysosomal escape, and logistical hurdles encompassing scalability, cost, and time. A multidisciplinary collaboration beyond the field of biology now extends to chemistry, physics, biomaterials, and nanotechnology, allowing rapid development of designer therapeutic EVs that are now entering late-stage human clinical trials.

Keywords:  bioengineering; exosomes; extracellular vesicles; heart; therapeutics

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323054
Adv Wound Care (New Rochelle). 2024 Jun 18.

Standardized Reporting of Research on Exosomes to Ensure Rigor and Reproducibility.

Anita Yadav, Yi Xuan, Chandan K Sen, Subhadip Ghatak.

SIGNIFICANCE: The study of extracellular vesicles (EV), especially exosomes, has unlocked new avenues in understanding cellular communication and potential therapeutic avenues.RECENT ADVANCES: Advancements in EV research have shown significant contributions from the International Society for Extracellular Vesicles (ISEV), in establishing methodological standards. The evolution of the MISEV guidelines from 2014 to 2023 reflects enhanced research rigor and reproducibility. The launch of EV-TRACK platform promotes uniformity and reproducibility by providing a centralized repository for data sharing and standardization practices. Furthermore, databases like EVpedia and ExoCarta have facilitated data sharing and collaboration within the scientific community. Concurrently, exosome-based therapies have emerged as a forefront area within regenerative medicine and targeted drug delivery, showcasing the potential of exosomes in promoting tissue regeneration.
CRITICAL ISSUES: Despite advancements, the field grapples with challenges such as vesicular heterogeneity, EV isolation complexity, and standardization. These issues impact research reproducibility and clinical applications. The inconsistency in exosomal preparations in clinical trials poses significant challenges to therapeutic efficacy and safety.
FUTURE DIRECTIONS: The review outlines critical areas for future research, including the need for technological innovation in EV isolation and characterization, the establishment of standardized protocols, and a deeper understanding of exosome biology. The review also highlights the need to reassess guidelines, develop new EV isolation and characterization technologies, and establish standardized protocols to overcome current limitations. Emphasis is placed on interdisciplinary research and collaboration to address the complexities of EV biology, improve clinical trial design, and ultimately realize exosome's therapeutic and diagnostic potential. Continued evaluation and rigorous scientific validation are essential for successful exosome integration.

DOI: https://doi.org/10.1089/wound.2024.0093
Res Sq. 2024 Jun 03. pii: rs.3.rs-4423565. [Epub ahead of print]

Characterization of exosome-mediated propagation of systemic inflammatory responses into the Central Nervous System.

Mahesh Chandra Kodali, Chinnu Salim, Saifudeen Ismael, Sarah Grace Lebovitz, Geng Lin, Francesca-Fang Liao.

The mechanisms through which systemic inflammation exerts its effect on the CNS are still not completely understood. Exosomes are small (30 to 100 nanometers) membrane-bound extracellular vesicles released by most of the mammalian cells. Exosomes play a vital role in cell-to-cell communication. This includes regulation of inflammatory responses by shuttling mRNAs, miRNAs, and cytokines both locally and systemically to the neighboring as well as distant cells to further modulate their transcriptional and/or translational states and affect the functional phenotype of those cells that have taken up these exosomes. The role of circulating blood exosomes leading to neuroinflammation during systemic inflammatory conditions was further characterized. Serum-derived exosomes from LPS-challenged mice (SDEL) were freshly isolated from the sera of the mice that were earlier treated with LPS and used to study SDEL effects on neuroinflammation. Exosomes isolated from the sera of the mice injected with saline were used as a control. In-vitro studies showed that the SDEL upregulate pro-inflammatory cytokine gene expression in the murine cell lines of microglia (BV-2), astrocytes (C8-D1A), and cerebral microvascular endothelial cells (bEnd.3). To further study their effects in-vivo, SDEL were intravenously injected into normal adult mice. Elevated mRNA expression of pro-inflammatory cytokines was observed in the brains of SDEL recipient mice. Proteomic analysis of the SDEL confirmed the increased expression of inflammatory cytokines in them. Together, these results further demonstrate and strengthen the novel role of peripheral circulating exosomes in causing neuroinflammation during systemic inflammatory conditions.

DOI: https://doi.org/10.21203/rs.3.rs-4423565/v1
Front Mol Biosci. 2024 ;11 1268019

Therapeutic potential of mesenchymal stem cell-derived exosomes in skeletal diseases.

Xiaobo Yang, Shaodian Zhang, Jinwei Lu, Xiaoling Chen, Tian Zheng, Rongxin He, Chenyi Ye, Jianbin Xu.

  Skeletal diseases impose a considerable burden on society. The clinical and tissue-engineering therapies applied to alleviate such diseases frequently result in complications and are inadequately effective. Research has shifted from conventional therapies based on mesenchymal stem cells (MSCs) to exosomes derived from MSCs. Exosomes are natural nanocarriers of endogenous DNA, RNA, proteins, and lipids and have a low immune clearance rate and good barrier penetration and allow targeted delivery of therapeutics. MSC-derived exosomes (MSC-exosomes) have the characteristics of both MSCs and exosomes, and so they can have both immunosuppressive and tissue-regenerative effects. Despite advances in our knowledge of MSC-exosomes, their regulatory mechanisms and functionalities are unclear. Here we review the therapeutic potential of MSC-exosomes for skeletal diseases.

Keywords:  MSC-exosomes; fracture; osteoarthritis; osteoporosis; skeletal disease

DOI:  https://doi.org/10.3389/fmolb.2024.1268019
Stem Cell Res Ther. 2024 Jun 18. 15(1): 174

CAR-T cell-derived exosomes: a new perspective for cancer therapy.

Farnaz Sani, Shabnam Shojaei, Seyed Amirhossein Tabatabaei, Mohammadhossein Khorraminejad-Shirazi, Mona Latifi, Mahsa Sani, Negar Azarpira.

  Chimeric antigen receptor (CAR)-T cell adoptive immunotherapy is a promising cancer treatment that uses genetically engineered T cells to attack tumors. However, this therapy can have some adverse effects. CAR-T cell-derived exosomes are a potential alternative to CAR-T cells that may overcome some limitations. Exosomes are small vesicles released by cells and can carry a variety of molecules, including proteins, RNA, and DNA. They play an important role in intercellular communication and can be used to deliver therapeutic agents to cancer cells. The application of CAR-T cell-derived exosomes could make CAR-T cell therapy more clinically controllable and effective. Exosomes are cell-free, which means that they are less likely to cause adverse reactions than CAR-T cells. The combination of CAR-T cells and exosomes may be a more effective way to treat cancer than either therapy alone. Exosomes can deliver therapeutic agents to cancer cells where CAR-T cells cannot reach. The appropriate application of both cellular and exosomal platforms could make CAR-T cell therapy a more practicable treatment for cancer. This combination therapy could offer a safe and effective way to treat a variety of cancers.

Keywords:  CAR-T cell; Cancer; Cell therapy; Exosome; Solid tumor

DOI:  https://doi.org/10.1186/s13287-024-03783-4
J Nanobiotechnology. 2024 Jun 18. 22(1): 340

Exosomes as drug delivery systems in glioma immunotherapy.

Xinqing Hao, Shiming Wang, Liang Wang, Jiaqi Li, Ying Li, Jing Liu.

  Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy.

Keywords:  Drug delivery systems; Exosomes; Glioma; Immunotherapy

DOI:  https://doi.org/10.1186/s12951-024-02611-4
Arch Oral Biol. 2024 May 27. pii: S0003-9969(24)00133-X. [Epub ahead of print]165 106012

Salivary exosomal microRNA profile as biomonitoring tool for diagnosis and prognosis of patients with head and neck squamous cell carcinoma: a systematic review.

Lorenzo Sanesi, Giorgio Mori, Giuseppe Troiano, Andrea Ballini, Felice Valzano, Mario Dioguardi, Lorenzo Lo Muzio, Marco Magalhaes, Vito Carlo Alberto Caponio.

  OBJECTIVE: Exosomes are extracellular vesicles found in saliva and other body fluids. These vesicles range in size from 30 to 150 nm and play a crucial role in intercellular communication, transporting different biomolecules, actively targeting cells. These vesicles regulate both physiological and pathological processes within recipient cells. MicroRNAs (miRs) are transported within exosomes and are delivered to target cells where they influence signaling pathways, taking on a crucial regulatory role in oncogenesis; for example, they are implicated in progression and infiltration of various cancers, such as head and neck squamous cell carcinoma (HNSCC).MATERIAL AND METHODS: A systematic literature search based on specific keywords, according to the PRISMA guidelines, was carried out on PubMed, Web of Science, Scopus, and Google Scholar. Only original articles were selected during this review. The risk of bias was assessed by QUADAS-2.
RESULTS: At the end of the selection process 9 articles were included. In these studies, 41 miRs showed differential expression between healthy subjects and patient with HNSCC. The techniques varied among studies for the extraction and analysis of exosomal miRs. We presented also salivary exosomal miRs pathways, to give insights about pathogenetic mechanisms.
CONCLUSIONS: Exosomal microRNA are promising biomarkers for HNSCC detection. MiR-10b-5p, miR-486-5p, miR-24-3p, miR-412-3p, and miR-512-3p are the most promising markers applicable to diagnostics, while miR-1307-5p and miR-519c-3p resulted overexpressed and correlated to worse survival outcomes.

Keywords:  Biomarkers; Diagnosis; Head and Neck Neoplasms; MicroRNAs; Mouth Neoplasms; Prognosis

DOI:  https://doi.org/10.1016/j.archoralbio.2024.106012
EXCLI J. 2024 ;23 634-654

Exosomes derived from colorectal cancer cells take part in activation of stromal fibroblasts through regulating PHLPP isoforms.

Fatemeh Khaloozadeh, Ehsan Razmara, Fatemeh Asgharpour-Babayian, Alireza Fallah, Reihaneh Ramezani, Fatemeh Rouhollah, Sadegh Babashah.

  Given that tumor cells primarily instigate systemic changes through exosome secretion, our study delved into the role of colorectal cancer (CRC)-secreted exosomal miR-224 in stromal reprogramming and its impact on endothelial cell angiogenesis. Furthermore, we assessed the potential clinical significance of a specific signature of circulating serum-derived miRNAs, serving as a non-invasive biomarker for CRC diagnosis. Circulating serum-derived miR-103a-3p, miR-135b-5p, miR-182-5p, and miR-224-5p were significantly up-regulated, while miR-215-5p, and miR-455-5p showed a significant down-regulation in CRC patients than in healthy individuals. Our findings indicated that the expressions of CAF-specific markers (α-SMA and FAP) and CAF-derived cytokines (IL-6, and SDF-1) were induced in fibroblasts stimulated with SW480 CRC exosomes, partly due to Akt activation. As a plausible mechanism, exosomal transfer of miR-224 from SW40 CRC cells may activate stromal fibroblasts, which in turn, may promote endothelial cell sprouting. The study identified PHLPP1 and PHLPP2 as direct targets of miR-224 and demonstrated that CRC-secreted exosomal miR-224 activates Akt signaling by regulating PHLPP1/2 in activated fibroblasts, thereby affecting the stromal cell proliferation and migration. This study established a panel of six-circulating serum-derived miRNAs as a non-invasive biomarker for CRC diagnosis. Also, we proposed a supporting model in which CRC-secreted exosomal miR-224 takes part in the stromal reprogramming to CAFs partly through regulating Akt signaling. This may affect the malignant biological behavior of activated stromal cells and thereby elicit a vascular response within the microenvironment of CRC cells. See also the graphical abstract(Fig. 1).

Keywords:  Akt signaling; PHLPPs; cancer associated fibroblasts; colorectal cancer; exosomes; miR-224

DOI:  https://doi.org/10.17179/excli2024-6926
Cells. 2024 May 21. pii: 886. [Epub ahead of print]13(11):

Analysis of MicroRNA Cargo in Circulating Extracellular Vesicles from HIV-Infected Individuals with Pulmonary Hypertension.

Aatish Mahajan, Sumedha Gunewardena, Alison Morris, Matthias Clauss, Navneet K Dhillon.

  The risk of developing pulmonary hypertension (PH) in people living with HIV is at least 300-fold higher than in the general population, and illicit drug use further potentiates the development of HIV-associated PH. The relevance of extracellular vesicles (EVs) containing both coding as well as non-coding RNAs in PH secondary to HIV infection and drug abuse is yet to be explored. We here compared the miRNA cargo of plasma-derived EVs from HIV-infected stimulant users with (HIV + Stimulants + PH) and without PH (HIV + Stimulants) using small RNA sequencing. The data were compared with 12 PH datasets available in the GEO database to identify potential candidate gene targets for differentially altered miRNAs using the following functional analysis tools: ingenuity pathway analysis (IPA), over-representation analysis (ORA), and gene set enrichment analysis (GSEA). MiRNAs involved in promoting cell proliferation and inhibition of intrinsic apoptotic signaling pathways were among the top upregulated miRNAs identified in EVs from the HIV + Stimulants + PH group compared to the HIV + Stimulants group. Alternatively, the downregulated miRNAs in the HIV + Stimulants + PH group suggested an association with the negative regulation of smooth muscle cell proliferation, IL-2 mediated signaling, and transmembrane receptor protein tyrosine kinase signaling pathways. The validation of significantly differentially expressed miRNAs in an independent set of HIV-infected (cocaine users and nondrug users) with and without PH confirmed the upregulation of miR-32-5p, 92-b-3p, and 301a-3p positively regulating cellular proliferation and downregulation of miR-5571, -4670 negatively regulating smooth muscle proliferation in EVs from HIV-PH patients. This increase in miR-301a-3p and decrease in miR-4670 were negatively correlated with the CD4 count and FEV1/FVC ratio, and positively correlated with viral load. Collectively, this data suggest the association of alterations in the miRNA cargo of circulating EVs with HIV-PH.

Keywords:  cocaine; extracellular RNA; pulmonary vascular disease; substance abuse

DOI:  https://doi.org/10.3390/cells13110886
Int J Pharm. 2024 Jun 15. pii: S0378-5173(24)00583-0. [Epub ahead of print]660 124349

Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.

Fei Wang, Shuheng Qin, Jiejie Zhang, Menglu Huang, Qin Liu, Peipei Xu, Yong Hu.

  The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.

Keywords:  Doxorubicin; Extracellular Vesicle; Fas/FasL; Nitric oxide; Tumor therapy

DOI:  https://doi.org/10.1016/j.ijpharm.2024.124349
Nanoscale. 2024 Jun 18.

Advances in engineered nanosystems: immunomodulatory interactions for therapeutic applications.

Rupam Khatua, Bibrita Bhar, Souradeep Dey, Chitra Jaiswal, Victoria J, Biman B Mandal.

Advances in nanotechnology have led to significant progress in the design and fabrication of nanoparticles (NPs) with improved therapeutic properties. NPs have been explored for modulating the immune system, serving as carriers for drug delivery or vaccine adjuvants, or acting as therapeutics themselves against a wide range of deadly diseases. The combination of NPs with immune system-targeting moieties has facilitated the development of improved targeted immune therapies. Targeted delivery of therapeutic agents using NPs specifically to the disease-affected cells, distinguishing them from other host cells, offers the major advantage of concentrating the therapeutic effect and reducing systemic side effects. Furthermore, the properties of NPs, including size, shape, surface charge, and surface modifications, influence their interactions with the targeted biological components. This review aims to provide insights into these diverse emerging and innovative approaches that are being developed and utilized for modulating the immune system using NPs. We reviewed various types of NPs composed of different materials and their specific application for modulating the immune system. Furthermore, we focused on the mechanistic effects of these therapeutic NPs on primary immune components, including T cells, B cells, macrophages, dendritic cells, and complement systems. Additionally, a recent overview of clinically approved immunomodulatory nanomedicines and potential future perspectives, offering new paradigms of this field, is also highlighted.

DOI: https://doi.org/10.1039/d4nr00680a
J Extracell Vesicles. 2024 Jun;13(6): e12465

Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer.

John D Mason, Ewan Marks, Shih-Jung Fan, Kristie McCormick, Clive Wilson, Adrian L Harris, Freddie C Hamdy, Chris Cunningham, Deborah C I Goberdhan.

  Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.

Keywords:  AREG; EGFR; Rab11a‐exosome; cetuximab; colorectal cancer; extracellular vesicle

DOI:  https://doi.org/10.1002/jev2.12465
Drug Discov Today. 2024 Jun 18. pii: S1359-6446(24)00186-7. [Epub ahead of print] 104061

Molecular insights to therapeutic in cancer: role of exosomes in tumor microenvironment, metastatic progression and drug resistance.

Shikshya S Panda, Rajeev K Sahoo, Sambit K Patra, Stuti Biswal, Bijesh K Biswal.

  Exosomes play a pivotal part in cancer progression and metastasis by transferring various biomolecules. Recent research highlights their involvement in tumor microenvironment remodeling, mediating metastasis, tumor heterogeneity and drug resistance. The unique cargo carried by exosomes garners the interest of researchers owing to its potential as a stage-specific biomarker for early cancer detection and its role in monitoring personalized treatment. However, unanswered questions hinder a comprehensive understanding of exosomes and their cargo in this context. This review discusses recent advancements and proposes novel ideas for exploring exosomes in cancer progression, aiming to deepen our understanding and improve treatment approaches.

Keywords:  Cancer; drug resistance; exosome; metastasis; tumor heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.drudis.2024.104061