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

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)-induced MASH mice, QRDP treatment not only attenuated hepatic fibrosis and normalized liver function but also provided substantial protection against lipotoxicity. This full-API nanotherapeutic platform represents a safe and effective multitarget strategy for comprehensive MASH intervention.