Single-Atom Nanozyme Driven Lactate Reversal Fuels Oxidative Metabolism and Represses Lactylation to Heal Diabetic...

In this study, single-cell RNA sequencing (scRNA-seq) analysis revealed that both reactive oxygen species (ROS) and excessive lactate accumulation play critical roles in sustaining the local chronic inflammatory microenvironment. Guided by these insights, we developed a phosphorus-doped single-atom iron nanozyme (Fe@CN-P) designed to overcome the long-standing challenge of achieving lactate oxidation with metal-based nanozymes. Phosphorus, acting as a stronger electron donor, effectively increases the electron density at the iron active center, thereby enhancing its proton-capture capacity. In Fe@CN-P, the downward shift of the Fe d-band center, coupled with the increased density of electronic states near the Fermi level, lowers the energy barrier for proton transfer in the rate-determining step, ultimately enabling the efficient conversion of lactate into pyruvate. Notably, the dual functions of lactate oxidation and ROS scavenging restore mitochondrial activity and establish a "reversal-reutilization" metabolic pathway. Our findings demonstrate that phosphorus-induced electronic redistribution at the iron center enables efficient catalytic lactate "reversal-reutilization," thereby driving metabolic reprogramming and epigenetic remodeling to regulate inflammation. This work illustrates how atomic-level electronic structure engineering can be integrated with biological metabolic processes, providing insights and theoretical foundations for the design of single-atom nanozymes with both precise electronic modulation and therapeutic functionality.