Protection of Framework Nucleic Acid Complexes via Regulating Ferroptosis on Myocardial Ischemia-Reperfusion Injury

Abstract

The pathogenesis of myocardial ischemia-reperfusion injury (MIRI) is a complex process involving multiple pathophysiological mechanisms, including mitochondrial dysfunction, oxidative stress, and ferroptosis. Therefore, MIRI continues to pose a significant obstacle in cardiovascular therapy. Curcumin (Cur), a natural polyphenolic compound with potent antioxidant and antiferroptosis properties, has therapeutic potential but is poorly soluble, unstable, and has low bioavailability. To address these issues, a tetrahedral framework nucleic acid (tFNA) piggybacked Cur (tFNA-Cur) drug delivery system was designed to achieve efficient drug delivery and synergistically amplify the therapeutic effect by utilizing the programmable nanostructures, excellent safety profile, high biocompatibility, and intrinsic antioxidant activity of tFNA. In vitro studies demonstrated that tFNA-Cur could effectively mitigate oxidative stress-induced injury in H9C2 cardiomyocytes by restoring the redox balance and inhibiting ferroptosis. In a rat MIRI model, tFNA-Cur demonstrated significant efficacy, including reduced infarct size, decreased Fe²⁺ accumulation, and inhibited MDA production, a marker of lipid peroxidation. At the molecular level, tFNA-Cur enhanced the production of antioxidant proteins (GPX4, HO-1) by modulating the KEAP1-Nrf2 signaling axis, while inhibiting the overproduction of mitochondrial reactive oxygen species (ROS). This achieved a synergistic multitargeted and effective suppression of cardiomyocyte ferroptosis during the MIRI process. This study emphasizes the value of tFNA-Cur as a promising nanotherapeutic strategy in treating MIRI. It provides new ideas and research directions for combining nucleic acid nanomaterials with natural compounds to treat MIRI.