A Redox‐Triggered Bispecific Supramolecular Nanomedicine Based on Peptide Self‐Assembly for High‐Efficacy and Low‐Toxic Cancer Therapy

Abstract Polo‐like kinase 1 (PLK1) and polo‐like kinase 4 (PLK4) are closely associated with the progression of several cancers, and their bispecific inhibitors can kill tumor cells effectively. Herein, a redox‐responsive bispecific supramolecular nanomedicine based on the self‐assembly of a cyclic peptide, termed as C‐1, targeting both PLK1 and PLK4 as a potent anticancer agent is reported. C‐1 is a cyclic peptide in response to reducing agents such as glutathione (GSH), which is constructed by a combined approach of pharmacophore modeling, molecular docking, and reversible cyclization. After entering the cytosol of cancer cell, the disulfide linkage is reduced by intracellular GSH, with the resulting linear conformation self‐assembling into bispecific nanofibers. C‐1 can lead to apoptotic cell death by inducing caspase‐3 activation and PARP cleavage in HeLa cells. Moreover, it suppresses the growth of HeLa cells in cell assays, and inhibits the progression of HeLa cells‐induced xenografts in nude mice without inducing notable side effects. This work provides a successful example of developing the redox‐responsive bispecific nanomedicine for high‐efficacy and low‐toxic cancer therapy.