Enzyme-Mimetic, Cascade Catalysis-Based Triblock Polypeptide-Assembled Micelles for Enhanced Chemodynamic Therapy

Peptides and their conjugates are appealing as molecular scaffolds for constructing supramolecular biomaterials from the bottom up. Through strategic sequence design and interaction modulation, these peptides can self-assemble into diverse nanostructures that can, in turn, mimic the structural and catalytic functions of contemporary proteins. Here, inspired by the histidine brace active site identified in the metalloenzyme, we developed a triblock polypeptide with a hydrophobic polyleucine segment, a hydrophilic polylysine segment, and a terminal oligohistidine segment. This polypeptide demonstrates tunable and adaptive self-assembly morphologies. Moreover, copper ions can interact with the oligohistidine chelator and mediate the supramolecular assembly, generating metal-ligand centers for redox flow. The triblock polypeptide-based peptide micelles show Fenton-type activity with high substrate affinity when coassembled with copper ions. We have also engineered therapeutic micelles by coassembling two polypeptides, one integrated with copper ions and the other conjugated with glucose oxidase. This coassembled nanoplatform shows high in vitro and in vivo antitumor efficacy through a mechanism that combines triggered starvation and chemodynamic therapy. The versatility of this polypeptide sequence, which is compatible with various metal ions and functional ligands, paves the way for a broad spectrum of therapeutic and diagnostic applications.