Cardiac-targeting peptide-modified Prussian blue nanozymes loaded with Astragaloside IV for efficient ICI-myocarditis therapy.

Abstract

Immune checkpoint inhibitor (ICI) therapy can trigger immune-related adverse events across multiple organs, and myocarditis remains among the most lethal cardiac manifestations, culminating in arrhythmias and heart failure. Current management primarily relies on ICI interruption and empirical immunosuppression, but this broad strategy lacks heart-targeted precision and does not specifically address the concurrent immune and oxidative components of myocardial injury. Two major challenges therefore remain: insufficient therapeutic exposure within inflamed myocardium and the need to restrain pathogenic immune activation while protecting stressed cardiomyocytes from oxidative damage. Astragaloside IV (AS-IV) is appealing for pleiotropic cardioprotection and immunoregulation, yet limited bioavailability and insufficient myocardial exposure constrain its in vivo efficacy. Here we develop AS@PB-CTP, a cardiac-homing nanozyme integrating Prussian blue (PB) with SOD/CAT/POD-like catalysis, an AS-IV payload, and a cardiac-targeting peptide (CTP). AS@PB-CTP attenuates oxidative stress-induced injury in H₂O₂-challenged HL-1 cardiomyocytes and modulated macrophage-associated phenotypes toward an M2-like state. In the anti-PD-1/cTnI myocarditis model, AS@PB-CTP preferentially accumulates in injured myocardium, reduces leukocyte infiltration and fibrosis, and improves ventricular function, with increased ejection fraction and fractional shortening. Mechanistically, transcriptomic and protein-level analyses identified PI3K-Akt-mTOR signaling as a treatment-associated pathway, while immune profiling revealed coordinated attenuation of splenic IFN-γ⁺CD8⁺ effector T-cell responses and cardiac macrophage-associated inflammation. Collectively, AS@PB-CTP represents a cardiac-targeted redox-immune nanotherapeutic platform that couples catalytic antioxidant activity with immune modulation for ICI-associated myocarditis.