A Dynamic DNA Nano-Antioxidant Targeting Galectin-3 Attenuates Liver Fibrosis via Reducing Macrophage Oxidative Stress.

Abstract

Liver cirrhosis represents a major global health challenge with significant socioeconomic implications. Oxidative stress-mediated injury plays a pivotal role in driving fibrotic progression, with hepatic macrophages serving as a dominant source of reactive oxygen species (ROS). Consequently, targeted suppression of macrophage-derived ROS presents a promising therapeutic strategy. Single-cell RNA sequencing analysis identified Galectin-3 as positively correlated with macrophage oxidative stress and ROS production. Here, a dynamic DNA nano-antioxidant (DDN) is developed for hepatic macrophage-specific small interfering RNA (siRNA) delivery targeting Galectin-3. DDN administration achieved a 3.92-fold reduction in Galectin-3 expression, with transcriptomic profiling revealing restoration of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) signaling and consequent attenuation of oxidative stress in macrophages. Pharmacokinetic assessment via IVIS imaging demonstrated superior hepatic accumulation of DDN, exhibiting 1.57- and 2.11-fold greater fluorescence intensity at 240 min post-injection compared to siRNA and tetrahedral framework nucleic acid (tFNA), respectively. In a carbon tetrachloride (CCl)-induced mouse model, intraperitoneal DDN administration significantly reduced macrophage oxidative burden, ROS generation, and M1 polarization, ultimately mitigating collagen deposition and fibrotic progression. These findings establish DDN as a potent and targeted therapeutic platform for liver fibrosis treatment.