Decoding Tumor Metabolic Dysregulation Through Single‐Cell Analysis Informs the Inverse Design of Therapeutic Nanozymes

Single‐node interventions often fail against tumor metabolic networks due to dynamic compensation and pathway redundancy, necessitating synergistic, multi‐node strategies. However, translating high‐dimensional single‐cell omics into physicochemical parameters for materials design remains a major challenge. Herein, a cross‐scale inverse design paradigm for therapeutic nanozymes is proposed that maps single‐cell metabolic demands onto quantum‐chemical descriptors. Using hepatocellular carcinoma (HCC) as a model, integrated single‐cell transcriptomic and metabolic flux analyses revealed a triple vulnerability network involving lactate accumulation, focal hypoxia, and oxidative stress imbalance. Guided by first‐principles calculations and multiparameter screening based on reaction energy barriers and Bader charge transfer, 260 candidate materials were evaluated. This screening identified a nitrogen–phosphorus dual‐coordinated gold single‐atom nanozyme (APNC) with exceptional lactate oxidase (LOX)‐, catalase (CAT)‐, and peroxidase (POD)‐like activities and strong piezoelectric polarization. In vitro and in vivo studies demonstrated that APNC remodels the HCC microenvironment by depleting lactate and alleviating hypoxia, thereby disrupting glycolysis and triggering immunogenic cell death (ICD). APNC‐mediated piezocatalytic therapy achieved 95% tumor inhibition in vivo. This inverse design strategy bridges single‐cell metabolic profiling and atomic‐scale material engineering, establishing a versatile framework for precision nanozyme development across tumors and metabolic disorders.