The biosafety of nanoparticles is gaining extensive attention due to their dichotomous effects in fields of biomedicine and atmospheric chemistry. A number of studies have been carried out focusing on the cytotoxicity of nanoparticles and their interactions with cells. However, the mechanism of nanoparticle-cell interactions remains unclear. Here, we review the latest progress in the study of nanoparticle-cell interactions from a cellular chemo-mechanical perspective. Cell mechanics play an important role in cell differentiation, proliferation, apoptosis, polarization, adhesion, and migration. An understanding of the effects of nanoparticles on cell mechanics is therefore needed in order to enhance comprehension of nanoparticle-cell interactions. Firstly, the main molecules and signal pathways related to mechanical chemistry are introduced from three perspectives: cell surface adhesion receptors, the cytoskeleton, and the nucleus. Specifically, integrins and cadherins play a critical role in sensing both the external mechanical force and the force of cell transmission. Actin and microtubules, which are two components of the cytoskeletal network, act as a bridge in mechanical conduction. The nucleus can also be mechanically stressed by the surrounding cytoskeleton through the contraction of the matrix. The nuclear envelope also plays important roles in sensing mechanical signals and in adjusting the morphology and function of the nucleus. We summarize the major nanoparticle-based tools used in the laboratory for the study of cell mechanics, which includes traction force microscopy, atomic force microscopy, optical tweezers, magnetic manipulation, micropillars, and force-induced remnant magnetization spectroscopy. In addition, we discuss the effects that nanoparticles have on cell mechanics. Nanoparticles interact with the adhesion of molecules on the cell membrane surface and on cell cytoskeletal proteins, which further affects the mechanical properties involved in cell stiffness, cell adhesion, and cell migration. Overall, the general conclusions regarding the effects of nanoparticles on cell mechanics are as follows: (1) Nanoparticles can affect cell adhesion by disrupting tight and adherent junctions, and by regulating cell-extracellular matrix adhesion; (2) Nanoparticles can interact with cytoskeletal proteins (actins and tubulins) leading to structural reorganization or disruption of microtubules and F-actin; (3) Cell stiffness changes with the structural reorganization of the cytoskeleton; (4) Cell migration ability can be affected through changes in the cytoskeleton, cell adhesion, and the expression of cell migration-related proteins/molecules. To develop the nano-biosafety evaluation system, future studies should attempt to gain a better understanding of the molecular mechanisms involved with regards to nanoparticles and cell mechanics. Ultimately, further development of new methods and technologies based on nano-mechanical chemistry for diagnosis and treatment purposes are expected, given the wide application of nanomaterials in the biomedical field.