Synthetic intracellular nanostructures enhance cytotoxic T cell function via 2 assembly-driven chemical engineering

Abstract

Nature achieves diverse biological functions through structure formation. Inspired by the controlled formation of polypeptide nanostructures in cells, synthetic methods have been developed to assemble artificial nanostructures and organelle-like compartments within living cells. While these synthetic intracellular assemblies have mostly been used to disrupt cellular processes, their potential to induce a gain of function within cells remains unexplored. Here, we introduce redox-sensitive isopeptides that transform into self-assembling linear peptides inside human cytotoxic T cells in response to intracellular levels of glutathione. The in situ formation of synthetic peptide nanostructures in cytotoxic T cells leads to cellular stiffening, establishing a direct interface between biochemically driven peptide assembly and mechanobiological effects. This change in biophysical properties, along with increased phosphorylation of signaling proteins associated with T cell activation, correlates with a significant enhancement in the efficacy of cytotoxic T cells to eliminate cancer cells. Our findings elucidate the cellular impact of synthetic peptide nanostructures assembled within living cytotoxic T cells and demonstrate their ability to modulate and enhance effector immune cell responses.