Chemokine-Guided Biomimetic Mn/Ce Nanozymes for Immunomodulation and Cardioprotection in Doxorubicin-Induced Cardiomyopathy.

Abstract

Doxorubicin-induced cardiomyopathy (DIC) remains a major dose-limiting complication of anthracycline chemotherapy, with no effective targeted therapies available. Emerging evidence suggests that maladaptive inflammation, driven by aberrant monocyte recruitment, synergizes with oxidative stress to exacerbate myocardial injury. In particular, the CCL2-CCR2 chemokine axis plays a pivotal role in inflammatory cell trafficking and disease progression. An engineered biomimetic nanozyme, termed CCR2-MM@Mn/CeZ, is developed for inflammation-targeted cardioprotection. This platform comprises a Mn/Ce co-doped ZIF-8 nanozyme core with intrinsic antioxidant activity, cloaked by macrophage membranes (MM) overexpressing CCR2. This design enables selective homing to inflamed myocardium via CCL2 recognition, prolonged cardiac retention, and simultaneous modulation of inflammatory and oxidative microenvironments. In a DIC mouse model, CCR2-MM@Mn/CeZ significantly enhances myocardial accumulation, suppresses pro-inflammatory macrophage infiltration, promotes M2 polarization, and reduces intracellular reactive oxygen species. Transcriptomic analysis further reveals coordinated downregulation of inflammatory pathways and restoration of redox and metabolic homeostasis. Meanwhile, Mn²⁺-mediated T1-weighted magnetic resonance imaging enables noninvasive visualization of myocardial targeting. Collectively, this chemokine-axis-guided biomimetic nanozyme integrates targeted delivery, immunomodulation, oxidative stress suppression, and diagnostic imaging, offering a promising strategy for DIC theranostics.