Prussian blue nanoparticles targeting multiple PANoptosome-mediated PANoptosis for myocardial ischemia-reperfusion injury therapy

The extensive crosstalk between pyroptosis, apoptosis, and necroptosis suggests that inhibiting one of them can lead to compensating for the other, thereby reducing therapeutic efficacy. Here, we identify Prussian blue (PB) nanoparticle as an effective PANoptosis inhibitor that binds to key proteins (RIPK1, ZBP1, and AIM2) to regulate multiple PANoptosomes, thereby comprehensively inhibiting pyroptosis, apoptosis, and necroptosis and blocking their crosstalk in myocardial ischemia-reperfusion injury (MIRI) therapy. This PANoptosis inhibitor significantly alleviated MIRI-induced cardiac functional impairment and adverse ventricular remodeling, promoted extracellular matrix repair and neovascularization, and prevented cardiomyocyte hypertrophy. Furthermore, it modulated mitochondrial metabolism and immune-inflammatory homeostasis, helping to block the crosstalk within PANoptosis. Specifically, single-nuclear transcriptome sequencing of human heart samples, molecular dynamics simulations, transcriptome sequencing analysis, medical imaging technology, and molecular biological methods comprehensively elucidated the role of PB as a PANoptosis inhibitor in MIRI therapy. This study provides a reference paradigm for exploring the role of PANoptosis in other diseases and a framework for studying nanobiological interactions to uncover broader nanomaterial mechanisms.