Native and bioengineered extracellular vesicles for cardiovascular therapeutics

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Abstract

Extracellular vesicles (EVs) are a heterogeneous group of natural particles with relevance for the treatment of cardiovascular diseases. The endogenous properties of these vesicles allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be engineered to enhance their stability, bioactivity, presentation and capacity for on target binding at both cell type and tissue levels. The therapeutic potential of native (i.e., EVs that were not modified via donor cell or direct modulation) and engineered (i.e. EVs that were modified either pre- or post-isolation or whose pharmacokinetics/presentation was altered using engineering methodologies EVs is still limitedly explored in the context of cardiovascular diseases. Efforts to tap into the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of molecular compound delivery. In this review, we outline the endogenous properties of EVs that make them natural delivery agents as well as those features that can be improved using bioengineering approaches. We also discuss the therapeutic applications of native and engineered EVs for cardiovascular applications and examine the opportunities and challenges that need to be addressed to advance this research area with an emphasis on clinical translation.

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Regulated portals of entry into the cell.

Sean D. Conner, Sandra Schmid (2003)

The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.

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Cellular internalization of exosomes occurs through phagocytosis.

Du Feng, Wen-Long Zhao, Yun-Ying Ye … (2010)

Exosomes play important roles in many physiological and pathological processes. However, the exosome-cell interaction mode and the intracellular trafficking pathway of exosomes in their recipient cells remain unclear. Here, we report that exosomes derived from K562 or MT4 cells are internalized more efficiently by phagocytes than by non-phagocytic cells. Most exosomes were observed attached to the plasma membrane of non-phagocytic cells, while in phagocytic cells these exosomes were found to enter via phagocytosis. Specifically, they moved to phagosomes together with phagocytic polystyrene carboxylate-modified latex beads (biospheres) and were further sorted into phagolysosomes. Moreover, exosome internalization was dependent on the actin cytoskeleton and phosphatidylinositol 3-kinase, and could be inhibited by the knockdown of dynamin2 or overexpression of a dominant-negative form of dynamin2. Further, antibody pretreatment assays demonstrated that tim4 but not tim1 was involved in exosomes uptake. We also found that exosomes did not enter the internalization pathway involving caveolae, macropinocytosis and clathrin-coated vesicles. Our observation that the cellular uptake of exosomes occurs through phagocytosis has important implications for exosome-cell interactions and the exosome intracellular trafficking pathway.

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Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.

Charles P. Lai, Osama Mardini, Maria Ericsson … (2014)

Extracellular vesicles (EVs) are nanosized vesicles released by normal and diseased cells as a novel form of intercellular communication and can serve as an effective therapeutic vehicle for genes and drugs. Yet, much remains unknown about the in vivo properties of EVs such as tissue distribution, blood levels, and urine clearance, important parameters that will define their therapeutic effectiveness and potential toxicity. Here we combined Gaussia luciferase and metabolic biotinylation to create a sensitive EV reporter (EV-GlucB) for multimodal imaging in vivo, as well as monitoring of EV levels in the organs and biofluids ex vivo after administration of EVs. Bioluminescence and fluorescence-mediated tomography imaging on mice displayed a predominant localization of intravenously administered EVs in the spleen followed by the liver. Monitoring EV signal in the organs, blood, and urine further revealed that the EVs first undergo a rapid distribution phase followed by a longer elimination phase via hepatic and renal routes within six hours, which are both faster than previously reported using dye-labeled EVs. Moreover, we demonstrate systemically injected EVs can be delivered to tumor sites within an hour following injection. Altogether, we show the EVs are dynamically processed in vivo with accurate spatiotemporal resolution and target a number of normal organs as well as tumors with implications for disease pathology and therapeutic design.