Squalene-adenosine nanoparticles enhance cardioprotection in myocardial infarction: Efficacy and mechanistic insights.

Reperfusion injury following myocardial infarction (MI) poses a significant challenge, as it can exacerbate heart failure despite being the primary treatment. Adenosine is a promising cardioprotective drug, but its rapid degradation in circulation limits its therapeutic potential. Here, we report the design of self-assembled squalene adenosine nanoparticles (SQAdNPs) as a novel strategy to enhance adenosine's therapeutic potential in MI. In a rat ischemia/reperfusion MI model, it was observed that fluorescent SQAd NPs accumulated in the ischemic myocardium for at least 24 h post-intravenous administration. We evaluated the cardioprotective efficacy of SQAd NPs alone and in combination with antioxidant vitamin E (SQAd/VitE NPs), while assessing the impact of pre- vs post-reperfusion administration. Both nanoparticles' formulations improved cardiac function after 3 months, but only SQAd NPs prevented infarct expansion and adverse left ventricle remodelling with no differences between pre- or post-reperfusion treatment administration. Transcriptome analysis revealed that SQAd NPs upregulated genes linked to calcium signalling (Stac), mitochondrial function, as well as angiogenesis (Uqcrb), and DNA regulation (Ddx49), supporting enhanced cardiomyocyte survival. Functional analysis further indicated activation of pathways involved in cardiac repair, including SCF-KIT and EPH-Ephrin signalling, both associated with myocardial protection. Self-assembled SQAd NPs thus offer a unique therapeutic approach for reperfusion injuries, with enhanced efficacy and reduced side effects.