The delivery of functional substrates into living cells is one of the main challenges in chemistry and biochemistry. In order to address this, we have developed two type of transporters: Cell-penetrating poly(disulfide)s (CPDs) and strained cyclic disulfides.^[1] The efficiency of uptake for both methods involves the underestimated thiol-mediated uptake coupled with counterion-mediated uptake for CPDs and ring tension release for strained cyclic disulfides. A large variety of compounds have been delivered by those transporters, from small molecules such as fluorophores^[1,2] to giant substrates such as liposomes and polymersomes.^[3] Different strategies are now being investigated to broaden the scope of substrates to be delivered such as the streptavidin/biotin technology, side-chain and terminator functionalization for CPDs, and new cyclic molecules for strained-promoted thiol-mediated uptake as presented in Figure 1.

Figure 1. Transporters for thiol-mediated uptake. Streptavidin complexes are formed with a biotinylated substrate and multiple CPDs or strained disulfides (A). The substrate can be directly attached to CPDs (B). Library of compounds for strained cyclic thiol-mediated uptake (C).

[1] Gasparini, G.; Bang, E.-K.; Montenegro, J.; Matile, S. Chem. Commun. 2015, 51, 10389-10402.
[2] Zong. L.; Bartolami, E.; Abegg, D.; Adibekian, A.; Sakai, N.; Matile, S. ACS Cent. Sci. 2017, in press.
[3] Chuard, N.; Gasparini, G.; Moreau, D.; Lörcher, S.; Palivan, C.; Meier, W.; Sakai, N.; Matile, S. Angew. Chem. Int. Ed. 2017, 54, 2947-2950.