Ru/CoMn-LDH@CTP nanozymes with catalytic antioxidant activity alleviate myocardial glucolipotoxicity through inhibition of lipid peroxidation.

Diabetic cardiomyopathy (DbCM), a severe complication of type 2 diabetes mellitus (T2DM), is driven by glucolipid metabolism dysregulation-induced oxidative stress and ferroptosis. Current clinical management, primarily relying on glucose-lowering agents, shows limited efficacy due to poor myocardial targeting efficiency and inability to intervene in these interconnected pro-death pathways. Here we develop a cardiac-targeting multifunctional nanozyme (Ru/CoMn-LDH@CTP) by loading Ru single atoms onto layered double hydroxides (LDHs) and conjugating with cardiac-targeting peptide (CTP) for DbCM treatment. This nanozyme exhibits synergistic superoxide dismutase/catalase-mimetic activities and acid stability for broad-spectrum reactive oxygen species (ROS) scavenging. CTP modification enables efficient myocardial targeting and lysosomal escape for mitochondrial delivery. In vitro, Ru/CoMn-LDH@CTP effectively alleviates glucolipotoxicity-induced oxidative damage, reducing mitochondrial ROS to 54.47% and cardiomyocyte apoptosis to 18.76% of those in the injury group. In a DbCM mouse model, the nanozyme selectively accumulates in cardiac lesions, attenuates oxidative damage, reduces fibrosis to 38.68% of the original level, thereby suppressing ventricular remodeling and promoting cardiac functional recovery. Mechanistically, Ru/CoMn-LDH@CTP inhibits ferroptosis by upregulating protective proteins (GPX4, xCT, and CAT), while downregulating ACSL1 and 4-HNE. This work presents a smart targeted nanozyme with multi-enzyme synergy and acid stability, offering a novel therapeutic strategy for DbCM and related cardiovascular diseases.