Laia Hernandez-Oller 1 , Joaquin Seras-Franzoso 1, Fernanda Andrade 1,2, Diana Rafael 1,2, Ibane Abasolo 1,2 , Petra Gener 1,2,* and Simo Schwartz Jr. 1,2,*

1 Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d’Hebron Institut de Recerca, Universitat Autònoma de
Barcelona, 08035 Barcelona, Spain; (L.H.-O.); (J.S.-F.); (F.A.); (D.R.); (I.A.)
2 Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, 50004 Zaragoza, Spain
* Correspondence: (P.G.); (S.S.J.);
Tel.: +34-93489-4055 (P.G. & S.S.J.)

Received: 30 September 2020; Accepted: 23 November 2020; Published: 26 November 2020


Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been
shown that, when CSCs are eliminated, the surrounding Di erentiated Cancer Cells (DCCs) may reverse their phenotype and gain CSC-like features to preserve tumor progression and ensure tumor survival. This strongly suggests the existence of paracrine communication within tumor cells. It is evidenced that the molecular crosstalk is at least partly mediated by Extracellular Vesicles (EVs), which are cell-derived membranous nanoparticles that contain and transport complex molecules that can a ect and modify the biological behavior of distal cells and their molecular background. This ability of directional transport of small molecules prospects EVs as natural Drug Delivery Systems (DDS). EVs present inherent homing abilities and are less immunogenic than synthetic nanoparticles, in general. Currently, strong e orts are focused into the development and improvement of EV-based DDS. Even though EV-DDS have already reached early phases in clinical trials, their clinical application is still far from commercialization since protocols for EVs loading, modification and isolation need to be standardized for large-scale production. Here, we summarized recent knowledge regarding the use of EVs as natural DDS against CSCs and cancer resistance.

Keywords: cancer stem cells; extracellular vesicles; drug delivery systems.

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