A pH-responsive Chitosan/PEGDA composite hydrogel encapsulating dihydromyricetin ZIF-8 nanoparticles for infarcted myocardial repair by inhibiting ferroptosis

Cardiomyocyte loss is substantial after myocardial infarction (MI). Given the heart's limited intrinsic regenerative capacity, this loss frequently triggers myocardial fibrosis, detrimental ventricular remodeling, and ultimately culminates in heart failure. Among post-MI cell death pathways, cardiomyocyte ferroptosis—driven by ischemia, hypoxia, and oxidative stress—is a major contributor. Here, we constructed a novel pH-responsive anti -ferroptotic hydrogel for MI repair: a chitosan/PEGDA composite hydrogel encapsulating dihydromyricetin (DHM)-laden zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (ZIF-8@DHM NPs), denoted as ZIF-8@DHM/CP hydrogel. In vitro investigations demonstrated that the ZIF-8@DHM/CP hydrogel exhibited remarkable reactive oxygen species (ROS) scavenging capacity and successfully mitigated ferroptosis in H9C2 cells via the Sirt1/Nrf2/GPX4 pathway. We investigated the in vivo effects of ZIF-8@DHM/CP hydrogel utilizing a rat MI model. After injection for 28 days, the ZIF-8@DHM/CP hydrogel markedly enhanced cardiac function recovery in infarcted rats compared to the PBS group (left ventricular ejection fraction increased from 28.17 ± 2.94% to 52.35 ± 5.79%, P < 0.05), and histological analysis showed significant preservation of left ventricular free wall thickness in the ZIF-8@DHM/CP hydrogel group (thickness increased from 0.67 ± 0.15 mm to 1.50 ± 0.18 mm, P < 0.05). The results demonstrated that the ZIF-8@DHM/CP hydrogel prevented ferroptosis in cardiomyocytes, exhibited ROS-scavenging and anti-inflammatory properties, enhanced recovery of cardiac function post-MI, and prevented unfavorable remodeling. In this study, we enhanced the mechanical properties of a chitosan hydrogel and imparted anti -ferroptosis activity by constructing a composite drug-loaded hydrogel, providing a new perspective and direction for using chitosan hydrogel to promote MI repair. Schematic illustration of the fabrication of ZIF‑8@DHM/CP hydrogel and its repair mechanism in myocardial infarction. • Novel MOF-based pH-responsive hydrogel targets cardiomyocyte ferroptosis for myocardial infarction therapy. • It inhibits ferroptosis via Sirt1/Nrf2/GPX4 pathway and elevates EF to 52.35% in infarcted rats. • The system attenuates post-MI cardiac remodeling and preserves ventricular wall integrity.