Acid‐Triggered Cascaded Responsive Supramolecular Peptide Alleviates Myocardial Ischemia‒Reperfusion Injury by Restoring Redox Homeostasis and Protecting Mitochondrial Function

Abstract Redox imbalance, including excessive production of reactive oxygen species (ROS) caused by mitochondrial dysfunction and insufficient endogenous antioxidant capacity, is the primary cause of myocardial ischemia‒reperfusion (I/R) injury. In the exploration of reducing myocardial I/R injury, it is found that protecting myocardial mitochondrial function after reperfusion not only reduces ROS bursts but also inhibits cell apoptosis triggered by the release of cytochrome c. Additionally, nuclear factor erythroid 2‐related factor 2 (Nrf2) is considered a potential therapeutic target for treating myocardial I/R injury by enhancing the cellular antioxidant capacity through the induction of endogenous antioxidant enzymes. In this study, a peptide‒drug conjugate OI‐FFG‐ss‐SS31(ISP) is developed by integrating the Nrf2 activator 4‐octyl itaconate (OI) and the mitochondria‐targeting protective peptide elamipretide (SS31), and its therapeutic potential for myocardial I/R injury is explored. The results showed that ISP could self‐assemble into nanofibers in response to the acidic microenvironment and bind to Keap‐1 with high affinity, thereby activating Nrf2 and enhancing antioxidant capacity. Simultaneously, the release of SS31 could improve mitochondrial function and reduce ROS, ultimately providing a restoration of redox homeostasis to effectively alleviate myocardial I/R injury. This study presents a promising acid‐triggered peptide‐drug conjugate for treating myocardial I/R injury.