Bioinspired cardiac-targeted metal-organic framework nanozyme for modulating inflammatory responses in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common heart failure type with poor prognosis. Its mechanisms are unclear, and specific diagnostic criteria and effective treatments are lacking. Recent studies have emphasized the impact of inflammation and oxidative stress on the occurrence and development of HFpEF. Anti-inflammatory interventions targeting oxidative stress show promise, but traditional antioxidants are insufficient. A biomimetic manganese-doped ZIF-8 nanozyme (MnZIF) was synthesized. It was further modified with atrial natriuretic peptide (ANP) to create a cardiac-targeted nanozyme, NanoAM. Its efficacy was evaluated in a murine HFpEF model induced by a high-fat diet and L-NAME. Assessments included echocardiography, pressure-volume loop analysis, histology, and transcriptomics. In vitro studies measured reactive oxygen species (ROS) scavenging, cytotoxicity, and glucose uptake mechanisms. NanoAM exhibited multi-enzyme mimetic (SOD/CAT) activity and demonstrated excellent cardiac targeting and biocompatibility in vivo. In HFpEF mice, NanoAM significantly alleviated diastolic dysfunction, lowered blood pressure, and reduced cardiac fibrosis and hypertrophy. Mechanistically, NanoAM effectively scavenged myocardial ROS and downregulated pro-inflammatory cytokines. Transcriptomic and biochemical analyses revealed that NanoAM suppressed the expression of SOCS3, leading to enhanced IRS1-AKT2 signaling and increased GLUT4 membrane translocation. This study develops a novel cardiac-targeted nanozyme that effectively ameliorates key pathologies in experimental HFpEF. Its therapeutic action involves a dual mechanism: direct ROS scavenging and modulation of the SOCS3-IRS1-AKT2 signaling axis to improve insulin resistance. These findings highlight the potential of multifunctional nanozymes as a promising strategy for tackling the complex pathophysiology of HFpEF.