Disulfide‐Linked/Peptide‐Incorporated Macrocycles: Unique Redox‐Responsiveness and Application for Intracellular Cargo‐Delivery

The use of disulfide-linked macrocycles for biomedicine applications was not explored, which is, at least partially, due to the lack of a straightforward strategy to incorporate a cell-surface binding ligand into the macrocycles for facilitating cellular uptake. Herein, we discover that twin disulfides consisting of a flexible peptide and a structurally rigid organic molecule can be transformed into stable and trimeric macrocycles upon triggering with thiols. The disulfide linked/peptide incorporated macrocycles are substantially more stable in weakly reducing environments compared to their non-cyclic analogues due to the cooperativity of the three interlinked disulfide bonds. We further demonstrated that the trimeric macrocycles can be a promising scaffold for the development of intracellular cargo-delivery systems by incorporating a cell-penetrating peptide into the macrocycles.