RNA interference (RNAi) therapy via lipid nanoparticles (LNPs) holds transformative potential for liver disorders, yet its clinical efficacy in fibrosis is hampered by inefficient activated hepatic stellate cell (HSC) targeting, insufficient bioactivity to remodel the pathological niche, and risks of exacerbating lipotoxicity. To address these limitations, we develop VZLNP which is engineered as the therapeutic agent to fibrosis based on a bioactive ionizable VZ-lipid to establish an antioxidant (vitamin-E)-metal ion (zinc ions, Zn(II)) synergistic network. Vitamin-E acts as the antioxidant to scavenge reactive oxygen species (ROS) and deactivate hepatic stellate cells (HSCs), while the incorporated Zn(II) reinforces LNP stability and exert direct anti-fibrotic effects by inhibiting collagen deposition and providing antioxidant defense. Crucially, beyond their individual functions, the two components synergistically upregulate the potential therapeutic target GADD45A, a stress-response protein in liver fibrosis pathogenesis. Leveraging this potent bioactivity and enhanced HSC uptake, VZLNP delivers siRNA targeting the collagen-specific chaperone HSP47, achieving exceptional therapeutic efficacy in vitro and in vivo. This platform salvages the fibrotic microenvironment from the brink of collapse through orchestrated multipathway modulation, redefining the role of LNPs from passive vehicles to active, rehabilitative nanomedicines.
[1]Jilin Univ, China Japan Union Hosp, Jilin Prov Int Joint Res Ctr Lymphat Vasc Dis, Changchun 130033, Peoples R China.
[2]Chinese Acad Sci, Natl Ctr Nanosci & Technol, Key Lab Standardizat & Measurement Nanotechnol, Beijing 100190, Peoples R China.
(8.0+极速模式)