Full Active Nanoplatform Restores ROS Homeostasis for Synergistic Therapy of Fatty Liver Disease via Dual Endogenous–Exogenous Pathways

作者：Ziyi Lin, Peng Xu, Yan Xu, Yixin Zheng, Huimin Li, Zixin Chen, Zhe Wang, Shaochen Song, Yuhao Liu, Zhao Yang, Ju Cui, Heyun Shen · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.5c15203 · 被引用次数：3 · 研究领域：Liver Disease Diagnosis and Treatment、Liver Disease and Transplantation、Liver Diseases and Immunity

The therapeutic potential of nanomaterials in metabolic dysfunction-associated steatohepatitis (MASH) management remains limited by suboptimal drug loading efficiency and insufficient modulation of the disease's multifactorial pathogenesis. To address these issues, we developed a fully active pharmaceutical ingredient (API)-based nanodrug designed for synergistic MASH therapy through three integrated mechanisms: dual modulation of reactive oxygen species (ROS) homeostasis via endogenous and exogenous pathways, mitigation of pathological lipid accumulation, and suppression of inflammatory cascades. The nanodrug (QRDP) system utilizes arginine-modified polydopamine as both a nanocarrier and intrinsic antioxidant and codelivery of quercetin and the mitochondrial uncoupler 2,4-dinitrophenol. QRDP eliminates more than 80% of ROS and increases hepatic glutathione levels by 1.5-fold through exogenous antioxidant delivery and endogenous ROS suppression via regulating mitochondrial proton channels. Additionally, QRDP-mediated mitochondrial uncoupling reduced intracellular lipid overload by 90% through inhibition of ATP synthesis, accompanied by significant decreases in serum total cholesterol (39%), triglycerides (30%), and free fatty acids (59%). Furthermore, QRDP significantly downregulated pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in vitro and in vivo, while restoring anti-inflammatory markers (Arg-1 and IL-10) to over 78% of baseline levels. In high-fat diet (HFD)-induce...