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Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles

Exogenus Therapeutics, S.A., Biocant Park, Núcleo 4, Lote 2, 3060-197 Cantanhede, Portugal
Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-531 Coimbra, Portugal
Center for Neurosciences and Cell Biology (CNC), University of Coimbra, 3004-517 Coimbra, Portugal
Institute for Interdisciplinary Research (3Is), University of Coimbra, 3030-789 Coimbra, Portugal
Author to whom correspondence should be addressed.
Academic Editors: Tak-Wah Wong and Wei-Peng Li
Membranes 2021, 11(9), 647;
Received: 29 June 2021 / Revised: 10 August 2021 / Accepted: 19 August 2021 / Published: 24 August 2021
The development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 1011 particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 1010 total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use. View Full-Text
Keywords: extracellular vesicles; umbilical cord blood; EV therapeutics; EV toxicity extracellular vesicles; umbilical cord blood; EV therapeutics; EV toxicity
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MDPI and ACS Style

Rodrigues, S.C.; Cardoso, R.M.S.; Gomes, C.F.; Duarte, F.V.; Freire, P.C.; Neves, R.; Simoes-Correia, J. Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles. Membranes 2021, 11, 647.

AMA Style

Rodrigues SC, Cardoso RMS, Gomes CF, Duarte FV, Freire PC, Neves R, Simoes-Correia J. Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles. Membranes. 2021; 11(9):647.

Chicago/Turabian Style

Rodrigues, Silvia C., Renato M.S. Cardoso, Claudia F. Gomes, Filipe V. Duarte, Patricia C. Freire, Ricardo Neves, and Joana Simoes-Correia. 2021. "Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles" Membranes 11, no. 9: 647.

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