Bioactive Materials, 30 Nov, 2025, DOI：https://doi.org/10.1016/j.bioactmat.2025.11.049

Chiral metal nanozyme-enabled SOD2 activation and siRNA delivery cooperatively mitigating chronic heart failure

Zekun Wang, Ruofei Zhang, Yanyu Hu, Qile Song, Xiaoyan Fu, Yifan Wang, Mei Chen, Kelong Fan, Cundong Fan, Dongdong Sun

Abstract

Doxorubicin (DOX) treatment can lead to intracellular iron overload in cardiomyocytes, triggering excessive generation of reactive oxygen species (ROS) and resulting in cardiotoxicity. Superoxide dismutase (SOD) effectively scavenges ROS, and its catalytic activity depends on the binding of metal ions at its active site. Therefore, enhancing the activity of metal-dependent SOD represents a promising strategy to inhibit ferroptosis in cardiomyocytes and alleviate DOX-induced chronic heart failure. In this study, we constructed a biomimetic chiral MnO₂ nanozyme co-modified with macrophage and platelet membranes (D/L-MnO₂@MM), enabling precise targeting of DOX-injured myocardial tissues. This nanozyme exhibited potent catalase-like and SOD-like activities, efficiently eliminating excessive local hydrogen peroxide (H₂O₂) and superoxide anions (O₂^•−). Notably, the D-enantiomeric nanozyme (D-MnO₂@MM) significantly enhanced endogenous SOD2 activity via Mn2+ ion release, thereby suppressing the accumulation of lipid peroxides. Furthermore, based on transcriptomic and proteomic analyses, we designed an siRNA targeting the Hmox1 gene (siHmox1) and successfully loaded it onto the nanozyme platform (siHmox1@D/L-MnO₂@MM). Both in vitro and in vivo experiments confirmed that the dual mechanism, SOD2 activation and Hmox1 silencing, effectively restored mitochondrial function, attenuated ferroptosis, and significantly improved cardiac function in a rat model of chronic heart failure. Collectively, this study proposes a novel ferroptosis-targeted therapeutic strategy based on a biomimetic chiral nanozyme, offering new insights and promising therapeutic potential for the treatment of DOX-induced cardiotoxicity.

Article link：https://www.sciencedirect.com/science/article/pii/S2452199X25005791?via%3Dihub