Precision Fishing for Enzyme-like Materials: Identifying and Engineering Mesoporous Catalytic Sites for Ferroptosis Induction

The discovery of nanomaterials with enzyme-like activities, termed nanozymes, holds the potential to revolutionize traditional inhibitor-based therapies. However, precise identification of nanozymes for specific substrates and uncovering their catalytic domains remain significant challenges. Here, we developed a "fishing" method that utilizes AFM probes coated with substrate baits, functioning as fishing rods to enable <i>in situ</i> visualization of enzymatic reactions on nanomaterial surfaces. Through this approach, we identified four nanozymes, including graphene oxides (GOs) exhibiting lipoxygenase (LOX)-like activity. Notably, mesopores were identified as key catalytic domains on GO surfaces, guiding the engineering of tailored porous GOs (tp-GOs) with enhanced LOX-like activity. The optimized tp-GOs catalyzed ferroptosis in cancer cells and suppressed hepatic tumor growth and metastasis in mice. Our findings open new avenues in drug discovery, shifting the paradigm from enzyme inhibition to promoting specific biochemical reactions using nanozymes.