CXCR4 Clustering Induced by Polymeric Nanothreads Impedes Cancer Cell Metastasis via PIEZO1‐Mediated Mechanotransduction

The way in which the antagonist binds to the target molecule affects the intervention of its downstream pathway. Previously, an antagonistic strategy for CXC chemokine receptor 4 (CXCR4) utilizing two polymeric nanothreads is developed that self-assemble into patches on the cell surface. These patches induce CXCR4 clustering, leading to a significantly enhanced antagonism compared to conventional monovalent or multivalent receptor binding. However, the underlying mechanism remains unclear. Here, the critical role of Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1) is revealed, a mechanically sensitive ion channel protein, in mechanotransduction during CXCR4 clustering-mediated antagonism. It is shown that the nanothreads patching on the cell surface trigger F-actin rearrangement, and generates mechanical stress, which subsequently activates PIEZO1. Conversely, the application of a PIEZO1 inhibitor significantly attenuates the CXCR4 antagonistic effect of nanothreads patching, resulting in less inhibition of downstream activities associated with epithelial-to-mesenchymal transition of cancer cells and their metastasis both in vitro and in vivo. This result highlights the involvement of PIEZO1-mediated mechanotransduction in amplifying CXCR4 antagonism through triggering receptor clustering.