Cell-penetrating polydisulfides (CPDs) emerged in 2014 as traceless alternatives to cell penetrating peptides (CPPs) as a tool for intracellular delivery.^[1] Replacement of the original peptidic scaffold with a disulfide chain allows CPDs to enter cell by thiol-mediated uptake (TMU) and be subsequently depolymerized by intracellular GSH. CPDs have been usually grown from thiolated cargoes successfully delivered in the intracellular environment.^[2] Despite many efforts, such grafting-from approach only works at high concentrations, above any biological utility. We have recently unlocked the possibility of grafting thiolated cargoes to the CPDs through a dynamic and covalent process operating at concentration < 1 μM. Although a broad screening of cargoes is still currently ongoing, this new bioconjugation opens the possibility of making CPDs the final traceless TMU tag, which has been missing for decades.

[1] G. Gasparini, E.-K. Bang, G. Molinard, D. V. Tulumello, S. Ward, S. O. Kelley, A. Roux, N. Sakai, S. Matile, J. Am. Chem. Soc. 2014, 136, 6069–6074.

[2] E.-K. Bang, G. Gasparini, G. Molinard, A. Roux, N. Sakai, S. Matile, J. Am. Chem. Soc. 2013, 135, 2088–2091.