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

TL;DR

Prussian blue nanoparticles block multiple cell death pathways in heart injury, improving recovery by targeting PANoptosomes and restoring heart function.

Contribution

Prussian blue nanoparticles are shown to inhibit multiple PANoptosome components, offering a novel multi-target therapy for myocardial injury.

Findings

PB@PM nanoparticles suppress pyroptosis, apoptosis, and necroptosis in myocardial ischemia-reperfusion injury.

PB@PM improves mitochondrial function and immune-inflammatory balance in injured hearts.

The study provides a multi-omics framework for understanding PANoptosis in cardiovascular diseases.

Abstract

The extensive crosstalk among pyroptosis, apoptosis, and necroptosis limits the efficacy of therapies targeting only one pathway. Here, we show that Prussian blue (PB) nanoparticles act as multi-target PANoptosis inhibitors by binding key PANoptosome components including RIPK1, ZBP1, and AIM2 through multimodal interactions, thereby concurrently suppressing pyroptosis, apoptosis, and necroptosis in myocardial ischemia-reperfusion injury (MIRI). Platelet membrane-coated PB nanoparticles (PB@PM) exhibit enhanced cardiac targeting and efficiently alleviate MIRI-induced cardiac dysfunction, adverse ventricular remodeling, and cardiomyocyte hypertrophy. Mechanistically, PB@PM disrupt PANoptosome assembly, scavenge reactive oxygen species, improve mitochondrial function, and restore immune-inflammatory homeostasis. By integrating single nucleus transcriptomics of human heart samples, molecular dynamics simulations, transcriptomics, medical imaging, and molecular validation, we systematically decipher the therapeutic mechanisms of PB-based PANoptosis inhibition. This study establishes an integrative multi-omics framework for exploring PANoptosis in cardiovascular diseases and provides a promising nanotherapeutic strategy for MIRI treatment.

Myocardial ischemia-reperfusion injury is driven by interconnected pyroptosis, apoptosis, and necroptosis, making single-pathway inhibition ineffective. The authors show Prussian blue nanoparticles block multiple PANoptosomes and restore mitochondrial and immune homeostasis, markedly reducing PANoptosis and improving cardiac repair.

Figures