Myocardial infarction is the leading cause of heart failure and mortality worldwide. While thrombolytic therapy and percutaneous coronary intervention can rapidly restore blood flow, reperfusion injury is inevitable [1], resulting in further myocardial damage for which effective treatments are still lacking. Therefore, a comprehensive understanding of the molecular mechanisms underlying myocardial ischemia/reperfusion (MI/R) injury is urgently needed to identify novel therapeutic targets and develop new treatment strategies.

During ischemia-reperfusion, oxidative stress plays a crucial role in cardiac damage [2]. Thioredoxin-interacting protein (TXNIP) is essential for maintaining cellular redox homeostasis [3], and is implicated in various biological processes and pathological conditions [4]. Our previous studies have shown that TXNIP contributes to impaired ischemic heart repair and angiogenesis [5], [6]. Similarly, animal studies have demonstrated that the upregulation of TXNIP during MI/R had adverse consequences [7]. However, the detailed mechanism remains to be fully elucidated. N6-methyladenosine (m6A), the most abundant mRNA modification, has been shown to affect mRNA splicing, stability, localization, and translations [8]. It has been recognized as a key regulator in the progression of MI/R injury [9], but its role in the modulation of TXNIP expression under pathological conditions is still unclear.

The use of small interfering RNAs for gene silencing has opened up new possibilities for drug development, but, their therapeutic potential is hindered by poor tissue-specific delivery. Exosomes, with their stable transport ability to penetrate biological barriers, and low immunogenicity compared to cell-based strategies [10], have emerged as promising carriers for coding and noncoding RNA [11], [12]. Exosomes have been shown to contain RNA induced silencing complex components [13], and can be utilized as potential vehicles for RNA interference delivery, due to not only their ability to transfer mRNA and miRNA between cells and induce changes in recipient cells, but also their remarkable abundance in a majority of the body fluids [14]. However, the lack of specific targeting of natural exosomes remains a challenge for heart-targeted RNA interference.

Therefore, the aim of the current study is to investigate the effect of m6A modification on TXNIP expression in MI/R injury and to explore the feasibility of siRNA delivery by exosomes to improve MI/R injury.