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 4 )‐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.