Cardiac-targeting Ru/CoMn-LDH@CTP nanozyme alleviates diabetic cardiomyopathy by inhibiting lipid peroxidation and ferroptosis.

Diabetic cardiomyopathy (DbCM), a severe complication of type 2 diabetes mellitus (T2DM), arises from glucolipid metabolism dysregulation, leading to oxidative stress and ferroptosis. Current clinical treatments, primarily glucose-lowering agents, offer limited efficacy due to poor myocardial targeting and their inability to simultaneously address these interconnected pro-death pathways. There's a critical need for targeted interventions that can effectively scavenge reactive oxygen species (ROS) and modulate ferroptosis in the heart.

Researchers developed a cardiac-targeting multifunctional nanozyme, Ru/CoMn-LDH@CTP, by loading Ru single atoms onto layered double hydroxides (LDHs) and conjugating them with a cardiac-targeting peptide (CTP). In vitro, they tested the nanozyme's ability to alleviate glucolipotoxicity-induced oxidative damage in cardiomyocytes. In vivo, a DbCM mouse model was used to assess the nanozyme's myocardial accumulation, oxidative damage attenuation, fibrosis reduction, and impact on ventricular remodeling and cardiac functional recovery. Molecular analyses included GPX4, xCT, CAT, ACSL1, and 4-HNE expression.

The Ru/CoMn-LDH@CTP nanozyme demonstrated synergistic superoxide dismutase/catalase-mimetic activities and acid stability, enabling broad-spectrum reactive oxygen species (ROS) scavenging. CTP modification facilitated efficient myocardial targeting and lysosomal escape for mitochondrial delivery. In vitro, the nanozyme effectively alleviated glucolipotoxicity-induced oxidative damage, reducing mitochondrial ROS to 54.47% and cardiomyocyte apoptosis to 18.76% of those in the injury group. In the DbCM mouse model, the nanozyme selectively accumulated in cardiac lesions, significantly attenuating oxidative damage. It reduced cardiac fibrosis to 38.68% of the original level, thereby suppressing ventricular remodeling and promoting cardiac functional recovery. Mechanistically, Ru/CoMn-LDH@CTP inhibited ferroptosis by upregulating protective proteins (GPX4, xCT, and CAT), while concurrently downregulating ACSL1 and 4-HNE.