The Dual-Faceted Role of Metal-Based Nanomaterials in Hepatic Fibrosis Therapy

Abstract: Hepatic fibrosis represents a pivotal transitional stage between hepatitis and cirrhosis or hepatocellular carcinoma, predominantly mediated by hepatic stellate cells (HSCs) activation, dysregulated extracellular matrix (ECM) deposition, and oxidative stress. Metal-based nanomaterials (MNMs) exhibit dualistic effects in liver fibrosis progression, owing to their high specific surface area, tunable morphology, surface functionalization potential, and quantum properties. On the one hand, MNMs hold substantial therapeutic and diagnostic potential: they enable precise targeted drug delivery (passive/active targeting to HSCs or hepatocytes), synergize with natural products to enhance bioavailability and multifaceted antifibrotic efficacy, remodel the fibrotic microenvironment via nanozyme-mediated reactive oxygen species (ROS) scavenging and hypoxia alleviation, and serve as core components of integrated theranostic platforms for noninvasive imaging and real-time treatment monitoring. Specifically, pure metals (Au, Pt), metal oxides (CeO 2 , Fe 3 O 4 , MnO 2 ), metal sulfide/ selenide/ telluride (MoS 2 ), and metal composites (ZIF-8) have demonstrated promising preclinical outcomes in inhibiting HSCs activation, reducing ECM deposition, and improving fibrosis staging accuracy. While demonstrating therapeutic potential, MNMs present significant fibrogenic risks. Inappropriate physicochemical characteristics (eg, non-biodegradable cores, excessive particle size, cationic surface charges) or improper administration routes may induce hepatic injury through multiple mechanisms, including oxidative stress-mediated damage, inflammatory responses, dysregulated apoptosis/autophagy, and impaired lipid metabolism. These effects ultimately exacerbate fibrosis via multiple signaling pathways, notably the TGF-β 1/Smad and MAPK/Akt-FoxO3 cascades. In conclusion, MNMs present a dualistic role in hepatic fibrosis management. While their therapeutic potential is well-established when properly engineered to optimize targeting specificity, biodegradability, and biocompatibility, their fibrogenic risks require systematic mitigation through rational design and comprehensive safety assessments. Future progress will depend on achieving optimal balance between these opposing effects to facilitate clinical translation, thereby enabling novel precision medicine approaches for fibrosis diagnosis and treatment. Keywords: nanoparticle, physicochemical properties, oxidative stress, hepatotoxicity, hepatic stellate cells, therapy fibrosis