MecHA-Nano · Understanding cell-nanoparticle interactions through mechanobiology

The clinical translation of nanoparticle-based therapies over the last decade has been hampered by issues such asinefficient targeting and limited therapeutic effect. This poor translational outcome calls for deeper understanding of thebiomechanics of cell-nanoparticle (cell-NP) interactions. Indeed, targeting mechanosensing-activated cell pathways issuitable for tuning cell fate and readdressing its functions, as mechanosensing components control the expression of genesinvolved in the cell’s migration, survival and resistance to drugs. Hippo pathway appears to be one of the most promisingmechanobiology pathway, as it is involved in pathological diseases and tissue regeneration. This project aims to address theresponse of this pathway on cells upon interaction with nanoparticles. Indeed, tuning cell mechanosensing withnanoparticles is likely to hold great potentiality to control cell functionalities. The first objective will be the synthesis ofnanoparticles of different size, shape and stiffness, using a silica scaffold coated with hyaluronic acid via metal-phenolicnetwork assembly with exceptional physicochemical properties. The second objective consists in the application of Superresolutionmicroscopy for studying cell-NP interactions with unprecedented detail and unveil the interaction/structure/spatiotemporal localization of mechanosensing components related to the Hippo pathway (i.e. YAP, actin and focaladhesions) at molecular level. The third objective will be the deep analysis of the molecular biology and biochemistry ofmechanosensing proteins (i.e. YAP, TAZ, RhoA and Rock), and their downstream effectors (i.e. TEAD and transcriptionalfactors) involved in the response to cell-NP interaction. The forth objective will pursue the analysis of these interactions usingNenoVision technology (LiteScope), for measuring cell stiffness at the boundary of cell-NP contact with unique resolution.