Circadian Rhythm-Dependent Therapy by Composite Targeted Polyphenol Nanoparticles for Myocardial Ischemia-Reperfusion Injury.

Myocardial ischemia-reperfusion (IR) injury is a severe rhythmic disease with a high prevalence in the early morning. IR injury has a significant circadian rhythm in reactive oxygen species (ROS) and inflammation levels. The development of rhythmic drugs has become a priority in myocardial IR injury. In this study, resveratrol (RES) and proanthocyanidins (OPC) were utilized to design nanoparticles (NPs), with hyaluronic acid (HA) as the core, grafted with MMP-targeting peptides to improve delivery to injured myocardial regions (HA-RES-OPC-MMP NPs). NPs significantly scavenged ROS, attenuated inflammation, and activated the rhythm gene. Notably, the difference in therapeutic effects on myocardial IR injury in mice at Zeitgeber time (ZT)1 and ZT13 confirms that NPs are rhythm-dependent drugs. At ZT13, echocardiographic and MRI confirm that IR injury in mice was not as severe as at ZT1, yet NPs were also less effective in treatment. Further, knockout mice confirmed the rhythm-dependent treatment of myocardial IR injury by NPs. Molecular studies have shown that rhythmic characteristics of inflammation and transcript levels are the main reasons for the different rhythmic therapeutic effects of NPs. Circadian rhythm-dependent treatment of HA-RES-OPC-MMP NPs has excellent potential for more precise treatment of myocardial IR injury in the future.