<i>In Situ</i> Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting

Abstract

Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSH-responsive <i>in situ</i> self-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created <i>via</i> the design of two peptides E3C16E6 and EVM^SeO derived from lipid-inspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive <i>in situ</i> self-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the <i>in situ</i> self-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.