Peptide-Directed Chiral Gold Nanozymes for Asymmetric Polymerization and Chirality-Selective Cytotoxicity

Precise control over macromolecular chirality is critical for molecular recognition and targeted biological interventions. Herein, we report a pair of chiral gold nanozymes (l-/d-AuNEs) that mimic horseradish peroxidase (HRP)-like activity to catalyze the oxidative coupling of chiral phenolic monomers in a cellular environment. By introducing peptide ligands with both amino-acid-based configurational chirality and secondary structural chirality, the nanozymes enable high-yield enantioselective polymerization of the chiral Ritodrine (RITO), leading to the formation of enantiomeric dimers and high-molecular-weight polymers. The resulting polymers, Poly-l-RITO and Poly-d-RITO, exhibit significantly enhanced cytotoxicity relative to the monomer, with Poly-d-RITO showing a notably higher pro-apoptotic effect. Mechanistic studies reveal that Poly-d-RITO preferentially accumulates at the cell membrane and induces more severe membrane damage. These findings reveal a chirality-dependent biointerface effect and highlight the potential of nanozyme-driven asymmetric polymerization as an alternative strategy for chiral drug development and targeted cancer therapy.