Nanocarrier Nanomechanics: A Key to Unlocking Endocytosis in Cancer Cells Navigating Epithelial–Mesenchymal Transition Dynamics

The mechanical properties of nanocarriers and the ability of tumor cells to sense mechanical cues are critical factors in regulating cellular internalization. During epithelial-mesenchymal transition (EMT), tumor cells undergo changes that enhance their invasiveness, but how these changes affect their ability to sense mechanical cues, thereby impacting drug delivery efficiency and treatment effects, is still unknown. Here, we synthesized chitosan nanoparticles (CSNPs) with different Young's moduli ranging from 0.325 to 18.25 MPa. Our findings revealed that as EMT progresses, tumor cells exhibited enhanced internalization capacity, attributing to the elevated integrin expression by EMT. During the cellular internalization of CSNPs with different Young's moduli, the stiffer CSNPs displayed more internalization in tumor cells. It was due to the upregulation of p-FAK expression after the integrin of cells sensed stronger mechanical cues generated by stiffer CSNPs, resulting in promoted F-actin polymerization, ultimately achieving more cellular internalization. After loading doxorubicin (DOX) into CSNPs (DOX-CSNPs), the stiffer DOX-CSNPs exhibited higher inhibitory ability, with mesenchymal phenotype tumor cells displaying the highest treatment effect. Taken together, our work demonstrated how the mechanical properties of nanocarriers affect cellular internalization across different EMT stages and provided a mechanical-based nanocarrier engineering strategy for cells undergoing EMT.