ROS-scavenging nanoparticles loaded with tectorigenin protect against acetaminophen-induced hepatotoxicity by interrupting the calcium/ROS-mediated pathogenic endoplasmic reticulum–Mitochondrial signaling cascade

Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI) and acute liver failure (ALF) worldwide, representing a major clinical and public health challenge due to its rapid onset and high morbidity. Current clinical treatment is limited to N-acetylcysteine (NAC), but its efficacy is highly time-dependent and the prolonged regimen imposes additional clinical burdens and side effects. Natural compounds hold tremendous promise for hepatoprotection, but their clinical translation is limited by unfavorable physicochemical and pharmacokinetic properties. In this study, tectorigenin (Tec), an isoflavone possessing anti-inflammatory and antioxidative activity, was encapsulated within a reactive oxygen species (ROS)-responsive nanoplatform (PBHB@Tec) to enhance bioavailability and enable site-selective hepatoprotection. PBHB@Tec possessed diameters compatible with passage through hepatic sinusoidal fenestrae into the space of Disse enabling direct hepatocyte interaction, while exhibiting potent ROS scavenging activity and undergoing ROS-triggered morphological degradation that accelerated Tec release under oxidative conditions. In an APAP-induced ALI mouse model, PBHB@Tec markedly attenuated ALI phenotypes. Mechanistically, PBHB@Tec reduced endoplasmic reticulum (ER) stress, which alleviated ER Ca²⁺ leak and subsequently prevented mitochondrial Ca²⁺ overload. This, in turn, lowered mitochondrial ROS production and restored antioxidant defenses, collectively disrupting the feedforward calcium/ROS apoptotic cascade. These broad improvements in ER-mitochondrial homeostasis positioning PBHB@Tec as a promising ROS-responsive nanotherapy for APAP-induced hepatotoxicity.