Bio-nano interactions have been extensively explored in nanomedicine to develop selective delivery strategies and reduce systemic toxicity. To enhance the delivery of nanocarriers to cancer cells and improve the therapeutic efficiency, different nanomaterials have been developed. However, the limited clinical translation of nanoparticle-based therapies, largely due to issues associated with poor targeting, requires a deeper understanding of the biological phenomena underlying cell-nanoparticle interactions. In this context, we investigate the molecular and cellular mechanobiology parameters that control such interactions. We demonstrate that the pharmacological inhibition or the genetic ablation of the key mechanosensitive component of the Hippo pathway, i.e., yes-associated protein, enhances nanoparticle internalization by 1.5-fold. Importantly, this phenomenon occurs independently of nanoparticle properties, such as size, or cell properties such as surface area and stiffness. Our study reveals that the internalization of nanoparticles in target cells can be controlled by modulating cell mechanosensing pathways, potentially enhancing nanotherapy specificity.

Departamento de Química Física Universidade de Vigo Campus Universitario As Lagoas Marcosende Vigo 36310 Spain

Department of Biochemistry Faculty of Science Masaryk University 62500 Brno Czech Republic

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

Faculty of Medicine Department of Biomedical Sciences Masaryk University 62500 Brno Czech Republic

Institute for Bioengineering of Catalonia 08028 Barcelona Spain

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

Molecular Medicine CEITEC Masaryk University 62500 Brno Czech Republic

Nanobiotechnology Core Facility CEITEC Masaryk University 62500 Brno Czech Republic

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

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