Extracellular Vesicles for Intracellular Drug Delivery

Bhagyashree Joshi

    Research output: ThesisThesis fully internal (DIV)

    188 Downloads (Pure)

    Abstract

    Extracellular vesicles (EVs) are nanoparticles released from cells, which play an important role in cell-cell communication. EVs cause phenotypic changes in recipient cells through the transfer of biomolecules (lipids, proteins, nucleic acids). However, the mechanism behind this cargo transfer is poorly understood. In this thesis, using a combination of light and electron microscopy, and a novel molecular probe-assay, we show that EVs are taken up by cells via endocytosis, and release their cargo via fusion with endosomes. In addition, we apply EV-mediated cargo transfer for the treatment of neurodegenerative diseases, in particular Huntington’s disease (HD), i.e., a protein aggregation disease. EVs loaded with the chaperone protein DNAJB6 are shown to reduce protein aggregation in cellular and in vivo models of HD. Proteomic analysis of the DNAJB6-EVs confirmed that they contain the DNAJB6 chaperone, but also other chaperones. Next, as EVs show intrinsic organotrophic properties, we explored EVs isolated from brain-trophic neural stem cells. Indeed, these EVs efficiently crossed the blood-brain barrier (BBB) in an in vitro BBB model, and carried encapsulated cargo along with them. This property could be attributed to their interactions with heparan sulfate proteoglycans at the BBB. Summarized, this thesis describes the development of EVs as vehicle for intracellular drug delivery, providing insight into EV transport across the BBB and mechanistic detail on the process of intracellular cargo delivery, while aiming at delivery of molecular chaperones as a therapeutic intervention for neurodegenerative diseases.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Zuhorn, Inge, Supervisor
    • van IJzendoorn, Sven C. D., Supervisor, External person
    Award date29-Mar-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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