Enzyme-Mimetic,\nCascade Catalysis-Based Triblock Polypeptide-Assembled\nMicelles for Enhanced Chemodynamic Therapy

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