Copper-Induced Supramolecular Peptide Assemblies for Multi-Pathway Cell Death and Tumor Inhibition.

Although self-assembly has emerged as an effective tool for fabricating biomaterials, achieving precise control over the morphologies and functionalities of the resultant assemblies remains an ongoing challenge. Inspired by the copper peptide naturally present in human plasma, in this study, we designed a synthetic precursor, FcGH. FcGH can self-assemble via two distinct pathways: spontaneous and Cu-induced. These two assembly pathways enabled the formation of assemblies with tunable morphologies by adjusting the amount of added Cu. We found that the nanoparticles formed by Cu-induced self-assembly exhibited a significantly higher cellular uptake efficiency than the wormlike fibers formed spontaneously. Moreover, this Cu-induced assembly process occurred spontaneously at a 1 : 1 molar ratio of Cu to FcGH, avoiding the excessive use of Cu and a tedious preparation procedure. By co-assembling with 10-hydroxycamptothecin (HCPT)-conjugated FcGH, Cu-induced supramolecular nanodrugs elicited multiple cell death modalities in cancer cells with elevated immunogenicity, enhancing the therapeutic effect compared to free HCPT. This study highlights Cu-induced self-assembly as an efficient tool for directing the assembly of nanodrugs and for synergistic tumor therapy.