Understanding cell-nanoparticle interactions through mechanobiology

ongoing

The clinical translation of nanoparticle-based therapies over the last decade has been hampered by issues such as inefficient targeting and limited therapeutic effect. This poor translational outcome calls for deeper understanding of the biomechanics of cell-nanoparticle (cell-NP) interactions. Indeed, targeting mechanosensing-activated cell pathways is suitable for tuning cell fate and readdressing its functions, as mechanosensing components control the expression of genes involved in the cell’s migration, survival and resistance to drugs. Hippo pathway appears to be one of the most promising mechanobiology pathway, as it is involved in pathological diseases and tissue regeneration. This project aims to address the response of this pathway on cells upon interaction with nanoparticles. Indeed, tuning cell mechanosensing with nanoparticles is likely to hold great potentiality to control cell functionalities. The first objective will be the synthesis of nanoparticles of different size, shape and stiffness, using a silica scaffold coated with hyaluronic acid via metal-phenolic network assembly with exceptional physicochemical properties. The second objective consists in the application of Superresolution microscopy 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 focal adhesions) at molecular level. The third objective will be the deep analysis of the molecular biology and biochemistry of mechanosensing proteins (i.e. YAP, TAZ, RhoA and Rock), and their downstream effectors (i.e. TEAD and transcriptional factors) involved in the response to cell-NP interaction. The forth objective will pursue the analysis of these interactions using NenoVision technology (LiteScope), for measuring cell stiffness at the boundary of cell-NP contact with unique resolution.