Synergy Between Cell‐Penetrating Peptides and Singlet Oxygen Generators Leads to Efficient Photolysis of Membranes

Cell‐penetrating peptides such as TAT or R9 labeled with small organic fluorophores can lyse endosomes upon light irradiation. The photoendosomolytic activity of these compounds can in turn be used to deliver proteins and nucleic acids to the cytosol of live cells with spatial and temporal control. In this report, we examine the mechanisms by which such fluorescent peptides exert a photolytic activity using red blood cells as a membrane model. We show that the peptides TAT and R9 labeled with tetramethylrhodamine photolyze red blood cells by promoting the formation of singlet oxygen in the vicinity of the cells' membranes. In addition, unlabeled TAT and R9 accelerate the photolytic activity of the membrane‐bound photosensitizer Rose bengal in trans, suggesting that the cell‐penetrating peptides participate in the destabilization of photo‐oxidized membranes. Peptides and singlet oxygen generators therefore act in synergy to destroy membranes upon irradiation.