Circadian Rhythm-Dependent\nTherapy by Composite Targeted\nPolyphenol Nanoparticles for Myocardial Ischemia-Reperfusion Injury

Myocardial ischemia-reperfusion (IR)\ninjury is a severe\nrhythmic\ndisease with a high prevalence in the early morning. IR injury has\na significant circadian rhythm in reactive oxygen species (ROS) and\ninflammation levels. The development of rhythmic drugs has become\na priority in myocardial IR injury. In this study, resveratrol (RES)\nand proanthocyanidins (OPC) were utilized to design nanoparticles\n(NPs), with hyaluronic acid (HA) as the core, grafted with MMP-targeting\npeptides to improve delivery to injured myocardial regions (HA-RES-OPC-MMP\nNPs). NPs significantly scavenged ROS, attenuated inflammation, and\nactivated the rhythm gene. Notably, the difference in therapeutic\neffects on myocardial IR injury in mice at Zeitgeber time (ZT)1 and\nZT13 confirms that NPs are rhythm-dependent drugs. At ZT13, echocardiographic\nand MRI confirm that IR injury in mice was not as severe as at ZT1,\nyet NPs were also less effective in treatment. Further, <i>Per1/2</i> knockout mice confirmed the rhythm-dependent treatment of myocardial\nIR injury by NPs. Molecular studies have shown that rhythmic characteristics\nof inflammation and <i>Sirt1</i> transcript levels are the\nmain reasons for the different rhythmic therapeutic effects of NPs.\nCircadian rhythm-dependent treatment of HA-RES-OPC-MMP NPs has excellent\npotential for more precise treatment of myocardial IR injury in the\nfuture.