Engineering frustrated Lewis pairs in copper nanoclusters for boosted enzyme-like catalysis and multi-analyte biosensing

Efficient substrate activation through engineered active sites, exemplified by frustrated Lewis pairs (FLPs), is a well-established strategy for developing high-performance enzyme-like catalysts. Herein, we report the rational design and synthesis of copper nanoclusters capped with 6-aza-2-thiothymidine (ATT)–denoted as CuNCs@ATT–featuring robust FLPs electrostatically modulated by the judicious ligand engineering. Within these FLP architectures, Cu serves as the Lewis acid (LA) and N as the Lewis base (LB). The pronounced electron-withdrawing capacity of the ATT ligand intensifies electrostatic interactions within the FLPs, culminating in the elongation of the O‒O bond in H 2 O 2 , which facilitates substrate activation and markedly enhances peroxidase-like (POD-like) catalytic activity. Moreover, leveraging this augmented POD-like activity, we engineer a sensor array that achieves precise identification and quantification of multiple non-steroidal anti-inflammatory drugs, including N-acetyl-p-aminophenol, ibuprofen, and acetylsalicylic acid, thereby circumventing the inherent limitation of selectivity in conventional nanozymes. This paradigm demonstrates the viability of ligand-engineered electrostatic modulation of FLPs for substrate activation and introduces a novel and rational design concept for the development of advanced nanozymes.