Efficient RNA drug delivery using red blood cell extracellular vesicles

SummaryExtracellular vesicles (EV) mediate intercellular signaling by transferring their cargo to recipient cells. Red blood cell (RBC)-derived EVs constitute a significant proportion of circulating EVs and have been implicated in regulating immune responses. Here, we describe a transgenic mouse model for fluorescent-based mapping of RBC-EV target cells based on the functional transfer of EV-contained Cre-recombinase to target cells. In a murine model of ischemic heart failure, we detect an increase in RBC-EV-targeted cardiomyocytes in the hearts and microglial cells in the brains. Cells targeted by RBC-EVs present an enrichment of genes implicated in cell proliferation and metabolism pathways compared to non-recombined (non-targeted) cells. Cardiomyocytes targeted by RBC-EVs are more likely to demonstrate cellular markers of DNA synthesis and proliferation, suggesting functional significance of EV-mediated signaling. In conclusion, we leverage our mouse model for mapping of RBC-EV targets in murine ischemic heart failure to demonstrate quantitative and qualitative changes in RBC-EV recipients.

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Clearance and phenotype of extracellular vesicles after red blood cell transfusion in a human endotoxemia model

Transfusion and Apheresis Science ◽

10.1016/j.transci.2019.05.008 ◽

2019 ◽

Vol 58 (4) ◽

pp. 508-511 ◽

Cited By ~ 2

Author(s):

Lisa van Manen ◽

Anna L. Peters ◽

P. Matthijs van der Sluijs ◽

Rienk Nieuwland ◽

Robin van Bruggen ◽

...

Keyword(s):

Blood Cell ◽

Extracellular Vesicles ◽

Red Blood Cell ◽

Red Blood Cell Transfusion ◽

Human Endotoxemia ◽

Endotoxemia Model

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A Polymer-Triton X-100 Conjugate Capable of PH-Dependent Red Blood Cell Lysis: A Model System Illustrating the Possibility of Drug Delivery Within Acidic Intracellular Compartments

Journal of Drug Targeting ◽

10.3109/10611869409015915 ◽

1994 ◽

Vol 2 (4) ◽

pp. 341-347 ◽

Cited By ~ 25

Author(s):

Ruth Duncan ◽

Paolo Ferruti ◽

Dionyssios Sgouras ◽

Anthony Tuboku-Metzger ◽

Elisabetta Ranucci ◽

...

Keyword(s):

Drug Delivery ◽

Blood Cell ◽

Red Blood Cell ◽

Cell Lysis ◽

Model System ◽

Intracellular Compartments ◽

Ph Dependent ◽

Triton X

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Syngeneic red blood cell–induced extracellular vesicles suppress delayed‐type hypersensitivity to self‐antigens in mice

Clinical & Experimental Allergy ◽

10.1111/cea.13475 ◽

2019 ◽

Vol 49 (11) ◽

pp. 1487-1499 ◽

Cited By ~ 5

Author(s):

Katarzyna Nazimek ◽

Eugenio Bustos‐Morán ◽

Noelia Blas‐Rus ◽

Bernadeta Nowak ◽

Włodzimierz Ptak ◽

...

Keyword(s):

Blood Cell ◽

Extracellular Vesicles ◽

Red Blood Cell ◽

Delayed Type Hypersensitivity ◽

Self Antigens

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Monocyte-mediated activation of endothelial cells occurs only after binding to extracellular vesicles from red blood cell products, a process mediated by β-integrin

Transfusion ◽

10.1111/trf.13851 ◽

2016 ◽

Vol 56 (12) ◽

pp. 3012-3020 ◽

Cited By ~ 14

Author(s):

Marleen Straat ◽

Maike E. van Hezel ◽

Anita Böing ◽

Anita Tuip-De Boer ◽

Nina Weber ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Cell ◽

Extracellular Vesicles ◽

Red Blood Cell

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Photoacoustic imaging of stimuli-responsive red blood cell drug delivery agents

2016 IEEE International Ultrasonics Symposium (IUS) ◽

10.1109/ultsym.2016.7728881 ◽

2016 ◽

Cited By ~ 1

Author(s):

Adam Dixon ◽

Justin Farry ◽

Johnny Chen ◽

Ali H. Dhanaliwala ◽

John A. Hossack ◽

...

Keyword(s):

Drug Delivery ◽

Blood Cell ◽

Red Blood Cell ◽

Photoacoustic Imaging ◽

Stimuli Responsive

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The Fluid Membrane determines Mechanics of Red Blood Cell Extracellular Vesicles and is Softened in Hereditary Spherocytosis

10.1101/212456 ◽

2017 ◽

Cited By ~ 1

Author(s):

Daan Vorselen ◽

Susan M. van Dommelen ◽

Raya Sorkin ◽

Jürgen Schiller ◽

Richard van Wijk ◽

...

Keyword(s):

Blood Cell ◽

Extracellular Vesicles ◽

Red Blood Cell ◽

Hereditary Spherocytosis ◽

Cell Communication ◽

Lipid Vesicle ◽

Bending Modulus ◽

Rbc Membrane ◽

Blood Disorder ◽

Healthy Donors

AbstractExtracellular vesicles (EVs) are widely studied regarding their role in cell-to-cell communication and disease, as well as for applications as biomarker or drug delivery vehicle. EVs contain both membrane and intraluminal proteins, affecting their structural properties and thereby likely their functioning. Here, we use atomic force microscopy for the mechanical characterization of red blood cell (RBC) EVs from healthy individuals as well as from a patient with hereditary spherocytosis (HS) due to ankyrin deficiency. We show that the EVs are packed with proteins, yet their response to indentation is similar to that of a fluid lipid vesicle lacking proteins. The bending modulus of RBC EVs of healthy donors is ~15kbT, agreeing well with the bending modulus of the RBC membrane. Surprisingly, whereas RBCs become more rigid in HS, the excreted vesicles of a patient with this blood disorder have a significantly (~50%) lower bending modulus than donor EVs. These results shed new light on the mechanism and effects of EV budding and may underlie the reported increase in vesiculation and stiffening of RBCs in hereditary spherocytosis patients.

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Red Blood Cell Extracellular Vesicle-Based Drug Delivery: Challenges and Opportunities

Frontiers in Medicine ◽

10.3389/fmed.2021.761362 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wararat Chiangjong ◽

Pukkavadee Netsirisawan ◽

Suradej Hongeng ◽

Somchai Chutipongtanate

Keyword(s):

Drug Delivery ◽

Blood Cell ◽

Red Blood Cell ◽

Large Scale ◽

Regulatory Protein ◽

Extracellular Vesicle ◽

Clinical Applications ◽

Target Cells ◽

Scale Production ◽

Advantages And Disadvantages

Recently, red blood cell-derived extracellular vesicles (RBCEVs) have attracted attention for clinical applications because of their safety and biocompatibility. RBCEVs can escape macrophages through the binding of CD47 to inhibitory receptor signal regulatory protein α. Furthermore, genetic materials such as siRNA, miRNA, mRNA, or single-stranded RNA can be encapsulated within RBCEVs and then released into target cells for precise treatment. However, their side effects, half-lives, target cell specificity, and limited large-scale production under good manufacturing practice remain challenging. In this review, we summarized the biogenesis and composition of RBCEVs, discussed the advantages and disadvantages of RBCEVs for drug delivery compared with synthetic nanovesicles and non-red blood cell-derived EVs, and provided perspectives for overcoming current limitations to the use of RBCEVs for clinical applications.

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