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Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

ABSTRACT: Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC-EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC-EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC-EVs in a C1q-dependent manner. RBC-EVs loaded with antisense oligonucleotides of microRNA-155 showed macrophage-dependent protective effects against acute liver failure (ALF) in a mouse model. These RBC-EVs were also effective in treatment of ALF. Furthermore, compared to routine doses of doxorubicin and sorafenib (SRF), RBC-EVs loaded with doxorubicin or SRF showed enhanced therapeutic effects on a murine model of orthotopic liver cancer through a mechanism dependent on macrophages. Importantly, drug-loaded RBC-EVs showed no systemic toxicity at therapeutically effective doses, whereas routine doses of doxorubicin and SRF showed obvious toxicity. Thus, drug-loaded RBC-EVs hold high potential for clinical applications in the treatment of liver disease therapy.

SUBMITTER: Zhang G

PROVIDER: S-EPMC7726052 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

Zhang Gensheng G Huang Xiaofang X Xiu Huiqing H Sun Yan Y Chen Jiming J Cheng Guoping G Song Zhengbo Z Peng Yanmei Y Shen Yingying Y Wang Jianli J Cai Zhijian Z

Journal of extracellular vesicles 20201209 2

Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC-EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC-EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC-EVs in a C1q-d ...[more]

PMID: 33335695

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Project description:In recent years, EVs have emerged as promising vehicles for coding and non-coding RNAs (ncRNAs), which have demonstrated remarkable potential as biomarkers for various diseases, including chronic liver diseases (CLDs). EVs are small, membrane-bound particles released by cells, carrying an arsenal of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other ncRNA species, such as piRNAs, circRNAs, and tsRNAs. These ncRNAs act as key regulators of gene expression, splicing, and translation, providing a comprehensive molecular snapshot of the cells of origin. The non-invasive nature of EV sampling, typically via blood or serum collection, makes them highly attractive candidates for clinical biomarker applications. Moreover, EV-encapsulated ncRNAs offer unique advantages over traditional cell-free ncRNAs due to their enhanced stability within the EVs, hence allowing for their detection in circulation for extended periods and enabling more sensitive and reliable biomarker measurements. Numerous studies have investigated the potential of EV-enclosed ncRNAs as biomarkers for CLD. MiRNAs, in particular, have gained significant attention due to their ability to rapidly respond to changes in cellular stress and inflammation, hallmarks of CLD pathogenesis. Elevated levels of specific miRNAs have been consistently associated with various CLD subtypes, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and chronic hepatitis B and C. LncRNAs have also emerged as promising biomarkers for CLD. These transcripts are involved in a wide range of cellular processes, including liver regeneration, fibrosis, and cancer progression. Studies have shown that lncRNA expression profiles can distinguish between different CLD subtypes, providing valuable insights into disease progression and therapeutic response. Promising EV-enclosed ncRNA biomarkers for CLD included miR-122 (elevated levels of miR-122 are associated with MASLD progression and liver fibrosis), miR-21 (increased expression of miR-21 is linked to liver inflammation and fibrosis in CLD patients), miR-192 (elevated levels of miR-192 are associated with more advanced stages of CLD, including cirrhosis and HCC), LncRNA HOTAIR (increased HOTAIR expression is associated with MASLD progression and MASH development), and LncRNA H19 (dysregulation of H19 expression is linked to liver fibrosis and HCC progression). In the present review, we focus on the EV-enclosed ncRNAs as promising tools for the diagnosis and monitoring of CLD of various etiologies.

Project description:Extracellular vesicles (EVs) have great potential as drug delivery vehicles. While mesenchymal/stromal stem cell (MSC) conditioned medium (CM) and milk are potentially safe and scalable sources of EVs for this purpose, the suitability of MSC EVs and milk EVs as drug delivery vehicles has never been compared and so was the objective of this study. Here EVs were separated from MSCs' CM and from milk and were characterised by nanoparticle tracking analysis, transmission electron microscopy, total protein quantification, and immunoblotting. An anti-cancer chemotherapeutic drug, doxorubicin (Dox), was then loaded into the EVs by one of three methods: by passive loading or by active loading by either electroporation or sonication. Dox-loaded EVs were analysed by fluorescence spectrophotometer, high-performance liquid chromatography (HPLC), and imaging flow cytometer (IFCM). Our study showed that EVs were successfully separated from the milk and MSC CM, with significantly (p < 0.001) higher yields of milk EVs/mL starting material compared to MSC EVs/mL of starting material. Using a fixed amount of EVs for each comparison, electroporation achieved significantly more Dox loading when compared to passive loading (p < 0.01). Indeed, of 250 µg of Dox made available for loading, electroporation resulted in 90.1 ± 12 µg of Dox loading into MSC EVs and 68.0 ± 10 µg of Dox loading into milk EVs, as analysed by HPLC. Interestingly, compared to the passive loading and electroporation approach, after sonication significantly fewer CD9+ EVs/mL (p < 0.001) and CD63+ EVs/mL (p < 0.001) existed, as determined by IFCM. This observation indicates that sonication, in particular, may have detrimental effects on EVs. In conclusion, EVs can be successfully separated from both MSC CM and milk, with milk being a particularly rich source. Of the three methods tested, electroporation appears to be superior for achieving maximum drug loading while not causing damage to EV surface proteins.

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Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

Publications

Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

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