Edge-rich Cu-N₃ single atom nanozyme drives lipid switching to potentiate tumor catalytic therapy

Tumor catalytic therapy represents a promising antitumor approach by inducing ferroptosis and overcoming apoptosis-related resistance mechanisms. Its efficacy is primarily dictated by the extent of membrane lipid peroxidation (LPO). However, tumor cells may evade ferroptosis through metabolic reprogramming that enriches monounsaturated fatty acids (MUFAs) in membrane lipids, thereby diminishing oxidative vulnerability. Hence, strategies that simultaneously enhance catalytic ROS production and reprogram lipid metabolism are required to address this challenge.

To overcome this limitation, a novel Cu-N₃ single-atom nanozyme with edge enrichment (ER-Cu₁SAZyme) was developed, characterized by a hollow porous structure and catalytically active sites concentrated along the edges. This design optimizes atom utilization, increases local electronic density, and lowers the reaction energy barrier, thereby promoting potent intracellular reactive oxygen species (ROS) generation. To further sensitize tumors to ferroptosis, ER-Cu₁SAZyme was combined with sirolimus (Srl), an FDA-approved drug, to create the Srl/ER-Cu₁SAZyme nanomedicine for coordinated catalytic and metabolic regulation.

The Srl/ER-Cu₁SAZyme formulation simultaneously inhibits stearoyl-CoA desaturase 1 (SCD1)-mediated MUFA synthesis and upregulates ACSL4, thereby shifting the membrane lipid composition toward a ferroptosis-sensitive phenotype and enhancing nanozyme-induced LPO. This dual catalytic-metabolic strategy increases ferroptosis susceptibility while reducing metastatic potential linked to excessive membrane fluidity. In tumor-bearing mouse models, Srl/ER-Cu₁SAZyme treatment led to a 33-fold reduction in tumor volume compared to the untreated group, without observable systemic toxicity.

These results highlight the effectiveness of integrating edge-enriched single-atom catalysis with lipid metabolic modulation to enhance ferroptosis-based tumor therapy. The Srl/ER-Cu₁SAZyme nanomedicine offers a safe and highly potent approach for dual catalytic-metabolic regulation in cancer treatment.