Conducting polymer-stabilized nanozymes alleviate sepsis-induced myocardial injury by inhibiting iron accumulation and lipid peroxidation

Abstract Septic cardiomyopathy (SC) is a severe complication of sepsis that significantly increases patient mortality. The onset of SC is associated with excessive reactive oxygen species (ROS), leading to increased oxidative stress and iron accumulation. Herein, we develop a library of conductive polypyrrole-polythiophene copolymer (PPy-co-PTh)-stabilized nanozymes by coordinating different metal ions within the copolymer framework. From this library, we identify a PPy-co-PTh stabilized ruthenium-based nanozyme (Ruzyme), which exhibits significant catalase- and superoxide dismutase-like activity, as well as nitrogen radical scavenging capability. Modifying the conductive interface significantly improves the catalytic activity and stability of the Ruzyme by lowering the catalytic energy barrier, reducing excessive oxidation caused by ROS, and facilitating the continuous decomposition of ROS. To achieve precise targeted delivery to myocardial mitochondria, (5-carboxypentyl) triphenyl phosphonium bromide  (TPP-COOH) and a cardiac-targeting peptide (CTP) are conjugated onto the surface of the Ruzyme. In vitro, the stabilized nanozymes effectively scavenge ROS, reduce iron accumulation, and inhibit iron-dependent cell death, thereby lowering lipid peroxidation. In male SC mice, they improve cardiac function, demonstrating therapeutic benefits. Given the growing interest in nanozymes for cardiovascular diseases, this study provides a potential foundation for the development of therapeutic agents for severe cardiomyopathy and related conditions.