Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell-nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple-negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.

Department of Bioanalytical Instrumentation CEITEC Masaryk University Brno 60200 Czech Republic

Department of Chemical Engineering The University of Melbourne Parkville Victoria 3010 Australia

Dipartimento di Scienze e Tecnologie Chimiche Università di Roma Tor Vergata Via Della Ricerca Scientifica Rome 00133 Italy

Electron Microscopy Facility Fondazione Istituto Italiano Di Tecnologia Via Morego 30 Genoa 16163 Italy

Faculty of Mechanical Engineering Brno University of Technology Technicka 2896 2 Brno 61669 Czech Republic

Institute for Bioengineering of Catalonia Barcelona Spain

International Clinical Research Center St Anne's University Hospital Brno 60200 Czech Republic

NenoVision Purkynova 649 127 Brno 61200 Czech Republic

School of Cardiovascular and Metabolic Medicine and Sciences King's College London London WC2R 2LS UK

School of Science RMIT University Melbourne 3000 Victoria Australia

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