Iron chelators loaded on myocardiocyte mitochondria-targeted nanozyme system for treating myocardial ischemia-reperfusion injury in mouse models

Ferroptosis plays a critical role in myocardial ischemia-reperfusion injury (MIRI), posing a significant clinical challenge. Nanoenzymes like cerium oxide (CeO₂) hold promise for mitigating oxidative damage and inhibiting ferroptosis, but their delivery efficiency and biological activity require optimization. This study aims to develop a targeted nanozyme delivery system for MIRI treatment by integrating CeO₂ with mesoporous polydopamine (mPDA) and dexrazoxane (DXZ) to achieve synergistic therapeutic effects. A biomineralization technique was used to synthesize CeO₂ nanoparticles (2-3 nm) within mPDA, forming ~ 130 nm composite nanoparticles (Ce@mPDA). Surface modifications with cardiac homing peptide (CHP) and triphenylphosphine (TPP) enabled hierarchical targeting to injured myocardium and mitochondria. DXZ-loaded Ce@mPDA-C/P nanoparticles (D/Ce@mPDA-C/P) were evaluated in vitro and in a MIRI mouse model for their effects on oxidative stress, ferroptosis, apoptosis, inflammation, and cardiac function. D/Ce@mPDA-C/P nanoparticles exhibited robust ROS scavenging, sustained DXZ release, and efficient myocardial and mitochondrial targeting. The D/Ce@mPDA-C/P system significantly reduced oxidative stress, upregulated GPX4 expression, inhibited ferroptosis, and modulated the inflammatory microenvironment. Long-term studies in a MIRI mouse model demonstrated reductions in myocardial fibrosis and improvements in cardiac function, including enhanced fractional shortening and ejection fraction. This hierarchical targeting delivery system effectively combines the antioxidant properties of CeO₂ with the iron-chelating effects of DXZ, providing a promising therapeutic strategy for MIRI. This approach may expand the clinical use of DXZ and advance nanomedicine-based interventions for myocardial repair.