Cell morphology and nucleus deformation are important when circulating tumor cells break away from the primary tumor and migrate to a distant organ. Cells are sensitive to the microenvironment and respond to the cell material interfaces. We fabricated TiO2 nanorod arrays with mesoscopic micro-nano interfaces through a two-step hydrothermal reaction method to induce severe changes in cell morphology and nucleus deformation. The average size of the microscale voids was increased from 5.1 to 10.5 mu m when the hydrothermal etching time was increased from 3 to 10 h, whereas the average distances between voids were decreased from 0.88 to 0.40 mu m. The nucleus of the MCF-7 cells on the TiO2 nanorod substrate that was etched for 10 h exhibited a significant deformation, because of the large size of the voids and the small distance between voids. Nucleus defromation was reversible during the cells proliferate process when the cells were cultured on the mesoscopic micro-nano interface.This reversible process was regulated by combining of the uniform pressure applied by the actin cap and the localized pressure applied by the actin underneath the nucleus. Cell morphology and nucleus shape interacted with each other to adapt to the microenvironment. This mesoscopic micro-nano interface provided a new insight into the cell-biomaterial interface to investigate cell behaviors.