Delivering therapeutic agents to cells is an important goal. This can be challenging, however, since many small molecules do not cross the cell membrane. One way to circumvent this problem is to use cell-penetrating peptides (CPPs), i.e. short peptide sequences that have the ability to cross the cell membrane and deliver cargo. Although it is critical that CPPs accomplish this task with minimal off-target effects, such actions have in many cases not been robustly screened. We presently investigated whether the commonly used CPPs Arg9 and Arg11 exert off-target effects on cellular calcium homeostasis. Our results show that these two CPPs reduce the activity of a calcium pump called SERCA2 that removes calcium from the cytosol. As this calcium pump is expressed in most cell types, reduction in its activity can have diverse unintended effects. Thus, our study indicates that we should be careful in using Arg9 and Arg11 to deliver therapeutic agents, or to deliver cargo to cells in our experiments.
https://pubmed.ncbi.nlm.nih.gov/37830576/
