Chimeric Nanocurved Materials Reprogram Receptor Signaling to Induce Apoptosis via a Curvature-Sensing Protein

Abstract

The nanoscale curvature of cell membranes plays a regulatory role in cell activity and response. This paper reports chimeric nanocurved materials functionalized with EGF that are capable of reprogramming growth factor signaling via a curvature-sensing protein. We achieved this by integrating epidermal growth factor (EGF) onto the surface of various nanostructured materials, which were exposed to the apical surface of cell membranes. These materials selectively triggered apoptosis, in contrast to flat EGF-modified surfaces. Serial variation of the nanoscopic parameters of the EGF-functionalized nanomaterials confirmed that the synergistic combination of the nanocurved material-mediated stimulation and receptor activation is critical for apoptosis induction. RNA-seq revealed a shift toward a pro-apoptotic gene expression profile, characterized by the suppression of survival-related pathways and enhancement of apoptosis-associated signals. Furthermore, gene editing experiments demonstrated that the nanocurved materials recruit the curvature-sensing protein PACSIN2, which in turn modulates the signaling cascade to induce apoptosis. Our findings show that chimeric nanocurved EGF-functionalized materials reprogram EGFR signaling from pro-survival to pro-apoptotic outcomes via an endocytosis-independent pathway mediated by PACSIN2. This mechanism underscores the potential of engineered biointerfaces to control receptor-mediated cell fate and suggests opportunities for patch-based anticancer therapies.