Exosome-mediated delivery of RNA and DNA for gene therapy

Munagala, Radha; Aqil, Farrukh; Jeyabalan, Jeyaprakash; Wallen, Margaret; Tyagi, Neha; Wilcher, Sarah A.; Yan, Jun; Schultz, David J.; Spencer, Wendy A.; Gupta, Ramesh C.

doi:10.1016/j.canlet.2021.02.011

Cited by 90 publications

(74 citation statements)

References 70 publications

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“…Lactoferrin extracted from breast milk is degraded to a pH of 2; however, when loaded into exosomes, lactoferrin is protected from proteolysis and then absorbed by intestinal cells (Lönnerdal et al, 2011). In other studies, the use of milk-derived exosomes to deliver siRNA targeting cancer genes has achieved good efficacy (Aqil et al, 2019;Munagala et al, 2021). Gene regulators delivered via breast milk-derived EVs generally present numerous advantages.…”

Section: Potential Application Of Milk-derived Evsmentioning

confidence: 99%

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Jiang

You

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are released by all cells under pathological and physiological conditions. EVs harbor various biomolecules, including protein, lipid, non-coding RNA, messenger RNA, and DNA. In 2007, mRNA and microRNA (miRNA) carried by EVs were found to have regulatory functions in recipient cells. The biological function of EVs has since then increasingly drawn interest. Breast milk, as the most important nutritional source for infants, contains EVs in large quantities. An increasing number of studies have provided the basis for the hypothesis associated with information transmission between mothers and infants via breast milk-derived EVs. Most studies on milk-derived EVs currently focus on miRNAs. Milk-derived EVs contain diverse miRNAs, which remain stable both in vivo and in vitro; as such, they can be absorbed across different species. Further studies have confirmed that miRNAs derived from milk-derived EVs can resist the acidic environment and enzymatic hydrolysis of the digestive tract; moreover, they can be absorbed by intestinal cells in infants to perform physiological functions. miRNAs derived from milk EVs have been reported in the maturation of immune cells, regulation of immune response, formation of neuronal synapses, and development of metabolic diseases such as obesity and diabetes. This article reviews current status and advances in milk-derived EVs, including their history, biogenesis, molecular contents, and biological functions. The effects of milk-derived EVs on growth and development in both infants and adults were emphasized. Finally, the potential application and future challenges of milk-derived EVs were discussed, providing comprehensive understanding and new insight into milk-derived EVs.

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Section: Potential Application Of Milk-derived Evsmentioning

confidence: 99%

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Jiang

You

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Unlike other nanoparticulate systems, exosomes possess special proteins in their membrane surface proteins that may help in the endocytosis, which, in turn, promotes the delivery of tethered content [17,18]. We have previously demonstrated the utility of bovine milk as a source of exosomes for the delivery of small-molecule drugs [19][20][21][22] and siRNA [23,24] and for the oral delivery of PAC to inhibit subcutaneous lung tumor xenografts [19]. Biocompatibility, cost-effectiveness and abundance are some of the hallmarks that make milk exosomes a potentially commercially viable option as a nanodrug carrier.…”

Section: Introductionmentioning

confidence: 99%

“…Colostrum powder provides higher yields of exosomes than mature milk. We have shown an overexpression of FRα and RFC in H1299 and A549 lung cancer cells; the overexpression of the folate receptors was more pronounced in tumor tissue versus normal lung tissue (100-fold overexpression) [24]. Here, exosomes, functionalized with folic acid (FA) to target tumor cells, are embedded with PAC (FA-ExoPAC), and the therapeutic efficacy of the formulation was compared with Abraxane for lung tumors grown in a tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes

Kandimalla

Alhakeem

Jeyabalan

et al. 2021

Cancers

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Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher amount of PAC compared to mature milk. Exosomal formulation of PAC (ExoPAC) showed higher antiproliferative activity and inhibition of colony formation against A549 cells compared with PAC alone, and also showed antiproliferative activity against a drug-resistant variant of A549. To further enhance its efficacy, exosomes were attached with a tumor-targeting ligand, folic acid (FA). FA-ExoPAC given orally showed significant inhibition (>50%) of subcutaneous tumor xenograft while similar doses of PAC showed insignificant inhibition. In the orthotopic lung cancer model, oral dosing of FA-ExoPAC achieved greater efficacy (55% growth inhibition) than traditional i.v. PAC (24–32% growth inhibition) and similar efficacy as i.v. Abraxane (59% growth inhibition). The FA-ExoPAC given i.v. exceeded the therapeutic efficacy of Abraxane (76% growth inhibition). Finally, wild-type animals treated with p.o. ExoPAC did not show gross, systemic or immunotoxicity. Solvent-based PAC caused immunotoxicity which was either reduced or completely mitigated by its exosomal formulations. These studies show that a tumor-targeted oral formulation of PAC (FA-ExoPAC) significantly improved the overall efficacy and safety profile while providing a user-friendly, cost-effective alternative to bolus i.v. PAC and i.v. Abraxane.

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“…93 , 94 , 95 Leucine-rich alpha-2-glycoprotein 1 (LRG1), basigin (BSG), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), and integrin beta-1 (ITGB1) were identified as clinical biomarkers for lung cancer. 96 , 97 , 98 , 99 Plasma or serum is an important component for liquid biopsy. The plasma protein level of HSP90β was validated as a potential prognostic biomarker in LUAD after a comprehensive proteomics analysis of 103 cases in China.…”

Section: The Application Of Quantitative Proteomics In Clinical Diagnosis and Treatmentmentioning

confidence: 99%

Quantitative proteomics characterization of cancer biomarkers and treatment

Yang

Shi

Zhang

et al. 2021

Molecular Therapy - Oncolytics

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Cancer accounted for 16% of all death worldwide in 2018. Significant progress has been made in understanding tumor occurrence, progression, diagnosis, treatment, and prognosis at the molecular level. However, genomics changes cannot truly reflect the state of protein activity in the body due to the poor correlation between genes and proteins. Quantitative proteomics, capable of quantifying the relatively different protein abundance in cancer patients, has been increasingly adopted in cancer research. Quantitative proteomics has great application potentials, including cancer diagnosis, personalized therapeutic drug selection, real-time therapeutic effects and toxicity evaluation, prognosis and drug resistance evaluation, and new therapeutic target discovery. In this review, the development, testing samples, and detection methods of quantitative proteomics are introduced. The biomarkers identified by quantitative proteomics for clinical diagnosis, prognosis, and drug resistance are reviewed. The challenges and prospects of quantitative proteomics for personalized medicine are also discussed.

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Exosome-mediated delivery of RNA and DNA for gene therapy

Cited by 90 publications

References 70 publications

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes

Quantitative proteomics characterization of cancer biomarkers and treatment

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