Abstract

Chronic heart failure (HF) remains a global health challenge due to the lack of therapies that effectively disrupt the pathological fibro-inflammatory networks driving disease progression. While current nanomedicine strategies often target intracellular pathways in isolated cell types, they overlook the multicellular crosstalk central to HF. Here, we develop scalably synthesized Prussian blue (PB) nanoparticles that selectively intercept the CCL2-CCR2 chemokine axis, a key pathway in fibroblast-macrophage communication. Single-nucleus RNA sequencing of murine and human failing hearts identifies a conserved pro-fibroinflammatory cardiac fibroblast subpopulation (POSTN hi CCL2 hi ) that recruits CCR2 + macrophages via CCL2 secretion. PB nanoparticles exhibit ultrahigh affinity (K D = 1.11 × 10 −10 m ) for free CCL2, inducing conformational distortion in its N-terminal domain via specific C≡N interface interactions with CRS1 residues, thereby blocking CCR2 engagement, a mechanism distinct from conventional nanomaterials. Although ineffective in monocultures, PB nanoparticles robustly improve cardiac function and remodeling in murine and translational porcine pressure-overload HF models, reducing left ventricular end-diastolic volume by 56.2% and fibrosis by 40.5%, while selectively depleting CCR2 + macrophages without systemic immunosuppression. Supported by scalable production (> 100 g/batch), long-term stability, and biosafety, this work establishes a cell communication-targeting nanomedicine strategy for network-driven diseases like HF.