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Chronic heart failure (HF) remains a global health challenge due to the lack of effective therapies that can disrupt the pathological fibro-inflammatory network that drives disease progression. Although current nanomedicine strategies often target intracellular pathways of isolated cell types, they neglect the multi-cellular interactions at the core of HF. We have developed scalable synthetic Prussian Blue (PB) nanoparticles that selectively block the CCL2-CCR2 chemokine axis, which is a key pathway for fibroblast-macrophage communication. Single-nucleus RNA sequencing of mouse and human failing hearts identified a conserved pro-fibrotic inflammatory cardiac fibroblast subset (POSTN hi CCL2 hi) that recruits CCR2+ macrophages by secreting CCL2. PB nanoparticles exhibit an extremely high affinity (K D = 1 × 10 −10 m) for free CCL2, interacting specifically with the C≡N interface and the CRS1 residue, inducing conformational distortion of its N-terminal domain, thereby blocking CCR2 binding. This mechanism is different from that of traditional nanomaterials. Although its effect is limited in a single culture, PB nanoparticles significantly improve cardiac function and remodeling in mouse and transgenic pig models of pressure-overload HF, reducing left ventricular end-diastolic volume by 56.2% and fibrosis by 40.5%, while selectively reducing CCR2+ macrophages without systemic immunosuppression. This work relies on scalable production (> batch 100 grams), long-term stability, and biosafety, establishing a cell communication-targeted nanomedicine strategy for network-driven diseases such as HF.
This study was published in Advanced Materials under the title "A Nano-Interception Strategy for Chronic Heart Failure: Prussian Blue Nanoparticles Disrupt Fibroblast-Immune Communication via CCL2 Sequestration". References:
DOI: 10.1002/adma.202520209
