Cardiac-targeted and ROS-responsive liposomes containing puerarin for attenuating myocardial ischemia-reperfusion injury

<b>Aim:</b> This study aimed to construct an ischemic cardiomyocyte-targeted and ROS-responsive drug release system to reduce myocardial ischemia-reperfusion injury (MI/RI). <b>Methods:</b> We constructed thioketal (TK) and cardiac homing peptide (CHP) dual-modified liposomes loaded with puerarin (PUE@TK/CHP-L), which were expected to deliver drugs precisely into ischemic cardiomyocytes and release drugs in response to the presence of high intracellular ROS levels. The advantages of PUE@TK/CHP-L were assessed by cellular pharmacodynamics, <i>in vivo</i> fluorescence imaging and animal pharmacodynamics. <b>Results:</b> PUE@TK/CHP-L significantly inhibited apoptosis and ferroptosis in H/R-injured cardiomyocytes and also actively targeted ischemic myocardium. Based on these advantages, PUE@TK/CHP-L could significantly enhance the drug's ability to attenuate MI/RI. <b>Conclusion:</b> PUE@TK/CHP-L had potential clinical value in the precise treatment of MI/RI. Myocardial ischemia-reperfusion injury (MI/RI) is a series of pathological changes caused by revascularisation after myocardial infarction, for which there is no effective treatment. Excessive production of reactive oxygen species (ROS) is an important predisposing factor for MI/RI. Apoptosis and ferroptosis of cardiomyocytes are important pathological mechanisms of myocardial ischemia-reperfusion injury and both are closely related to excessive intracellular ROS. We have successfully synthesized ROS-responsive and cardiac-targeted liposomes loaded with puerarin (PUE@TK/CHP-L). It was found that PUE@TK/CHP-L could target ischemic myocardium. <i>In vivo</i> and <i>ex vivo</i> results showed that PUE@TK/CHP-L can effectively reduce the level of myocardial oxidative stress and decrease cardiomyocyte apoptosis and ferroptosis. These results suggested that PUE@TK/CHP-L could hopefully be a promising drug carrier for mitigating MI/RI.