Ischemic heart disease is a serious threat to human health and one of the leading causes of death worldwide (Nowbar et al., 2019). Myocardial ischemia is a pathological state in which the blood flow to the heart is reduced, resulting in a reduction in the oxygen supply to the heart and a disruption in myocardial energy metabolism (Turer and Hill, 2010). Current research shows that oxidative stress is closely associated with myocardial ischemia. Myocardial cells will produce a large amounts of reactive oxygen species (ROS) under the conditions of ischemia and hypoxia. When ROS production exceeds the normal scavenging capacity of the body, excessive ROS will directly or indirectly cause abnormalities in myocardial structure and function, leading to cardiac oxidative stress damage (Althunibat et al., 2022, Jiang et al., 2021). Additionally, during myocardial ischemia, upregulated pro-inflammatory factors such as TNF-α, IL-1β and IL-6 can induce an excessive inflammatory response, cause cardiomyocyte apoptosis, exacerbate myocardial tissue damage, and impede cardiac repair (Liu et al., 2021, Meeran et al., 2021, Nagoor Meeran et al., 2020). Thereby, drugs with both antioxidant and anti-inflammatory functions will provide new avenues for the prevention and treatment of myocardial ischemia.

Apigenin (Apn) is a natural flavonoid compound found in many plants in the form of a yellow plant pigment. Examples include Matricaria recutita, Melissa axillaris, Perilla frutescens and Verbena officinalis. Studies show that Apn is a natural antioxidant that can not only eliminate exogenous ROS, but also regulate the endogenous antioxidant mechanism of cells and inhibit oxidative stress damage to the body (Fu et al., 2021, Mara de Menezes Epifanio et al., 2020, Sang et al., 2017). A large number of studies also show that Apn can play cardioprotective functions by inhibiting myocardial oxidative stress damage, such as inhibiting atherosclerosis, preventing myocardial fibrosis and myocardial ischemia injury (Clayton et al., 2021, Feng et al., 2021, Thangaiyan et al., 2018, Wang et al., 2019). Therefore, Apn is a good cardiac protector and has a medical prospect.

When myocardial cells become ischemic and anoxic, alterations in energy metabolism, ion channels and other mechanisms occur. Subsequently, extensive aseptic inflammatory reaction take place in these cells, leading to activation of Advanced glycation end products (AGEs), NF-κB and other signaling pathways, ultimately resulting in cell necrosis (Frangogiannis, 2012). AGEs are a group of pro-inflammatory compounds that have the potential to stimulate cells and cause oxidative stress, which may be closely associated with cardiovascular diseases (Arshi et al., 2023, Chen et al., 2022, Zheng et al., 2022). The receptor for advanced glycation end products (RAGE) is one of the receptors for AGEs, which can form stable compounds with AGEs, leading to NF-κB activation and participation in the proinflammatory/proapoptotic process of myocardial ischemia (Wasim et al., 2022, Zhang et al., 2022a, Zhang et al., 2022b). Small interfering RNA (siRNA) is a technology that silence genes, allowing for the inhibition of target gene expression by introducing double-stranded RNA to trigger homologous mRNA degradation (Friedrich and Aigner, 2022, Yuan et al., 2022). Therefore, siRNA of RAGE (siRAGE) can inhibit the production of inflammatory factors in myocardial cells by targeting the RAGE gene.

Myocardial ischemia has more causative factors and complex pathogenesis. In this study, based on the two therapeutic perspectives of oxidative stress and inflammatory response, we utilized the antioxidant properties of Apn flavonoid compounds to scavenge ROS from cardiomyocytes to reduce oxidative stress injury in the heart, and also to block ROS-induced inflammatory factors. Moreover, we also used siRNA gene silencing technology to specifically inhibit the upstream inflammatory factor target RAGE, effectively reducing the activation and secretion of inflammatory factors and preventing the occurrence of myocardial inflammatory response. Therefore, this combination of Apn and siRAGE both inhibits oxidative stress damage and prevents inflammatory responses, resulting in a dual therapeutic effect in ameliorating myocardial injury.

Nanotechnology is a material technology, and in modern medicine, the gradual nanosizing of drugs can improve drug solubility, drug utilization efficiency, and physiological barrier penetration. Cationic liposome is a gene and drug delivery system with good biocompatibility, low immunogenicity, and can be loaded with foreign gene fragments. It is widely used as a drug carrier to deliver nucleic acid (Kiaie et al., 2022, Kulkarni et al., 2018, Zhao et al., 2022). In this paper, cationic long-lasting liposomes (P-CLP-A/R) co-loaded with Apn and siRAGE were prepared using polyethylene glycol (PEG)-modified cationic lipid nanoparticles as carriers. Meanwhile, a model of isoprenaline (ISO)-induced myocardial ischemic injury was established, and the protective effect of P-CLP-A/R against myocardial ischemic injury was investigated by cell and animal experiments, providing theoretical basis and data support for its use as a novel lipid-integrated drug against ischemic heart disease.