Enhanced Ferritin-Manganese Interaction by Nanoplatinum Growth Enabling Liver Fibrosis 3D Magnetic Resonance Visualization and Synergistic Therapy with Real-Time Monitoring

Abstract

Early detection and timely intervention are essential to prevent liver fibrosis from progressing to cirrhosis or hepatocellular carcinoma. Herein, utilizing the enhanced ferritin-manganese interaction by nanoplatinum growth, a novel ferritin-platinum-manganese magnetic resonance nanoplatform with RGD grafting and metformin loading (FNMMR) is developed. RGD can enhance the targeting ability of the nanoplatform toward integrin αVβ3 on activated hepatic stellate cells (aHSCs) in liver fibrosis. Systemic delivery of FNMMR shows clear degree-dependent magnetic resonance contrast enhancement in liver fibrosis. 3D reconstruction techniques and histogram-based features are achieved to qualitatively and quantitatively analyze the inhomogeneous liver fibrosis areas. FNMMR with catalase-like activity can catalyze the generation of O₂ to alleviate the liver fibrosis hypoxia and inhibit the expression of HIF-1α, blocking the TGF-β1/Smad signaling pathway. In addition, metformin shows synergy with HIF-1α reduction in blocking the TGF-β1/Smad pathway, effectively inhibiting the activation of HSCs and reducing collagen formation. Furthermore, FNMMR can achieve real-time anti-fibrotic therapy monitoring by magnetic resonance imaging. Importantly, no obvious side effects can be observed in both histological and hematology examinations. Therefore, this work presents a novel nanoplatform for accurate liver fibrosis diagnosis and synergistic anti-fibrotic therapy with real-time monitoring.