School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
ACS Nano. 2024 Oct 15;18(41):28154-28169. doi: 10.1021/acsnano.4c07690. Epub 2024 Oct 7.
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.
心肌缺血再灌注（IR）损伤是一种严重的节律性疾病，清晨高发。IR 损伤的活性氧（ROS）和炎症水平具有显著的昼夜节律。节律性药物的开发已成为心肌 IR 损伤治疗的重点。本研究利用白藜芦醇（RES）和原花青素（OPC）设计纳米颗粒（NPs），以透明质酸（HA）为核心，接枝 MMP 靶向肽，以改善对损伤心肌区域的递送（HA-RES-OPC-MMP NPs）。NPs 显著清除 ROS，减轻炎症，激活节律基因。值得注意的是，在 Zeitgeber 时间（ZT）1 和 ZT13 时，对小鼠心肌 IR 损伤的治疗效果存在差异，证实 NPs 是依赖节律的药物。在 ZT13 时，超声心动图和 MRI 证实小鼠的 IR 损伤不如 ZT1 时严重，但 NPs 的治疗效果也较差。进一步，敲除小鼠证实了 NPs 对心肌 IR 损伤的节律依赖性治疗。分子研究表明，炎症的节律特征和 转录水平是 NPs 节律性治疗效果不同的主要原因。HA-RES-OPC-MMP NPs 的昼夜节律依赖性治疗为未来更精确地治疗心肌 IR 损伤提供了巨大潜力。
