Cell-Penetrating Peptide–Bismuth Bicycles

Cell-penetrating peptides (CPPs) play a significant role in the delivery of cargos into human cells for a wide range of therapeutic and diagnostic applications. We disclose the first CPPs based on peptide–bismuth bicycles, which can be readily obtained from commercially available peptide precursors, making them highly accessible for a wide range of applications. These CPPs enter mammalian cells with high efficiency as demonstrated by live-cell microscopy using fluorescently labelled peptides. We report highly efficient sequences that demonstrate comparable cellular uptake to conventional CPPs, despite requiring only three positive charges. Bicyclization triggered by the presence of bismuth(III) increases cellular uptake by more than one order of magnitude. Through the analysis of cell lysates using inductive coupled plasma mass spectrometry (ICP-MS), we have introduced an alternative approach to examine the cellular uptake of CPPs without the use of fluorescent dyes. This has allowed us to confirm the presence of bismuth in cells after exposure to our CPPs.