# 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.

## Key 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.