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Title: Endosomal escape of nucleic acids from extracellular vesicles mediates functional therapeutic delivery
Authors: Pham, TT 
Chen, H
Nguyen, PHD 
Jayasinghe, MK
Le, AH 
Le, MT 
Keywords: Extracellular vesicles
Drug delivery
Endosomal escape
Issue Date: 1-Feb-2023
Publisher: Elsevier BV
Citation: Pham, TT, Chen, H, Nguyen, PHD, Jayasinghe, MK, Le, AH, Le, MT (2023-02-01). Endosomal escape of nucleic acids from extracellular vesicles mediates functional therapeutic delivery. Pharmacological Research 188 : 106665-. ScholarBank@NUS Repository.
Abstract: Extracellular vesicles hold great promise as a drug delivery platform for RNA-based therapeutics. However, there is a lack of experimental evidence for the intracellular trafficking of nucleic acid cargos, specifically, whether they are capable of escaping from the endolysosomal confinement in the recipient cells to be released into the cytosol and hence, interact with their cytoplasmic targets. Here, we demonstrated how red blood cell-derived extracellular vesicles (RBCEVs) release their therapeutic RNA/DNA cargos at specific intracellular compartments characteristic of late endosomes and lysosomes. The released cargos were functional and capable of knocking down genes of interest in recipient cells, resulting in tumor suppression in vitro and in an acute myeloid leukemia murine model without causing significant toxicity. Notably, surface functionalization of RBCEVs with an anti-human CXCR4 antibody facilitated their specific uptake by CXCR4+ leukemic cells, leading to enhanced gene silencing efficiency. Our results provide insights into the cellular uptake mechanisms and endosomal escape routes of nucleic acid cargos delivered by RBCEVs which have important implications for further improvements of the RBCEV-based delivery system.
Source Title: Pharmacological Research
ISSN: 1043-6618
DOI: 10.1016/j.phrs.2023.106665
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