Hyaluronic acid-coated metal-organic framework for co-delivery of Sirtuin 3 gene and zinc to inhibit liver fibrosis.

Abstract

Liver fibrosis is characterized by excessive accumulation of extracellular matrix and disruption of hepatic sinusoidal architecture. However, effective therapies targeting microvascular dysfunction and immune imbalance remain limited. In this study, we present hyaluronic acid (HA)-coated zeolitic imidazolate framework-8 (ZIF-8) formulations (HDZs) loaded with sirtuin 3 (SIRT3) plasmid DNA, designed for the co-delivery of SIRT3 and bioavailable zinc ions to restore hepatic homeostasis. The HA coating promoted cellular uptake across multiple hepatic cell types, including hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and macrophages. In vitro, the nanoplatform suppressed stellate cell activation, maintained LSEC fenestrae, and induced macrophage polarization toward an anti-inflammatory phenotype. The pH-responsive disassembly of ZIF-8 enabled efficient intracellular release of SIRT3, while the simultaneous release of zinc ions contributed to cytoprotective effects. In fibrotic mouse models, the treatment significantly reduced collagen deposition, preserved sinusoidal structure, and promoted M2-dominant macrophage polarization, accompanied by improved liver function and elevated hepatic zinc levels. These results demonstrate a combined anti-fibrotic effect achieved through coordinated genetic modulation and micronutrient support. Collectively, this HDZ platform represents a multifunctional non-viral gene delivery strategy for liver fibrosis and offers potential for treating other chronic liver diseases involving mitochondrial dysfunction, immune dysregulation, and microvascular injury. STATEMENT OF SIGNIFICANCE: Liver fibrosis lacks effective treatments that simultaneously address structural damage, immune imbalance, and mitochondrial dysfunction. This study introduces a hyaluronic acid-coated ZIF-8 nanoplatform that co-delivers a mitochondrial regulatory gene and bioavailable zinc, enabling coordinated genetic and micronutrient modulation within the fibrotic liver. Unlike conventional approaches that target a single pathway or cell type, this platform engages hepatic stellate cells, liver sinusoidal endothelial cells, and macrophages, leading to reduced fibrosis, preserved sinusoidal architecture, and immune reprogramming in vivo. By integrating non-viral gene delivery with controlled zinc release, this work provides a multifunctional strategy for restoring hepatic homeostasis and expands the therapeutic potential of metal-organic framework-based nanomedicine for chronic liver diseases.