Targeting Ferroptosis with Polyphenolic Carbon Dots to Attenuate Myocardial Ischemia-Reperfusion Injury by Reducing Iron Accumulation and Enhancing Antioxidant Defense

Despite the widespread application of percutaneous coronary intervention in acute myocardial infarction, one-year mortality and heart failure rates remain unacceptably high, primarily driven by myocardial ischemia-reperfusion (I/R) injury. Ferroptosis, which predominantly occurs during late reperfusion, significantly contributes to adverse outcomes. Here, we rationally designed and synthesized polyphenolic carbon dots derived from resveratrol (Res-CDs) using an alkali-assisted carbonization approach. Res-CDs effectively suppressed ferroptosis by reducing iron accumulation and enhancing antioxidant defense, conferring robust cardioprotection in cellular and rat models of myocardial I/R injury. Mechanistically, Res-CDs activated the Nrf2 pathway, driving nuclear translocation and subsequent upregulation of antioxidant and iron metabolism-related genes. Notably, Res-CDs circumvented the pharmacokinetic limitations of native resveratrol while exhibiting favorable biocompatibility both in vitro and in vivo. Collectively, these findings establish Res-CDs as a promising nanotherapeutic strategy for myocardial I/R injury and underscore the potential of polyphenolic carbon dots in advancing cardiovascular disease treatment.