Single-cell RNA sequencing (scRNA-seq) revealed that reactive oxygen species (ROS) and excessive lactate accumulation sustain chronic inflammation. Guided by this, we developed phosphorus-doped single-atom iron nanozyme (Fe@CN-P) to overcome challenges in lactate oxidation using metal-based nanozymes. Phosphorus, as a stronger electron donor, increased the electron density of the iron active center, enhancing proton capture. In Fe@CN-P, the downshifted Fe d-band center and increased electron states near the Fermi level reduced proton transfer energy barriers, enabling efficient lactate-to-pyruvate conversion. The dual function of lactate oxidation and ROS scavenging restored mitochondrial activity and established a "reversal-reutilization" metabolic pathway. Our findings demonstrate that phosphorus-induced electron redistribution in the iron center enables efficient lactate catalysis, driving metabolic reprogramming and epigenetic remodeling to regulate inflammation. This work highlights how atomic-level electronic engineering integrates with biological metabolism, providing insights for designing single-atom nanozymes with precise electronic modulation and therapeutic functions.

Summary

A study published in ACS Nano reports that phosphorus-doped single-atom iron nanozyme (Fe@CN-P) efficiently repairs diabetic chronic wounds by targeting lactate metabolism and epigenetic remodeling. Single-cell sequencing revealed that ROS and lactate accumulation in the diabetic wound microenvironment drive macrophage dysfunction and chronic inflammation. By doping phosphorus, the team modulated the Fe active center’s electronic structure, shifting the Fe d-band center downward and increasing electron density near the Fermi level, which significantly lowered the energy barrier for lactate-to-pyruvate conversion, endowing the nanozyme with high LOX-like activity. Fe@CN-P also exhibited CAT-, SOD-, and POD-like activities, enabling dynamic pH-responsive antibacterial and antioxidant functions.

Mechanistically, Fe@CN-P restored mitochondrial function by scavenging ROS and converted lactate into pyruvate for TCA cycle "reutilization", establishing a "reversal-reutilization" metabolic pathway. Reduced lactate levels further inhibited H3K18la histone lactylation in macrophages, downregulating pro-inflammatory genes (FGR, IL-1α, MMP9) via epigenetic remodeling. In a diabetic wound infection model, Fe@CN-P-loaded GelMA hydrogel accelerated wound closure, reduced bacterial load, promoted M2 macrophage polarization, and enhanced angiogenesis. This work reveals how phosphorus doping tunes single-atom nanozyme electronic structure to regulate the metabolism-epigenetics axis, offering a dual-functional strategy for diabetic wound healing.

Reference News:

DOI: 10.1021/acsnano.5c20192

Click to read the original text, which will take you to the original link