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

## TL;DR

A new nanoparticle system protects against liver damage from acetaminophen overdose by reducing harmful reactive oxygen species and restoring cellular balance.

## Contribution

A ROS-responsive nanoplatform enhances the efficacy of tectorigenin for treating acetaminophen-induced liver injury.

## Key findings

- PBHB@Tec nanoparticles reduced endoplasmic reticulum stress and mitochondrial calcium overload in liver cells.
- The nanotherapy disrupted the calcium/ROS apoptotic cascade, lowering liver injury in a mouse model.
- ROS-triggered degradation of the nanoparticles improved drug release and antioxidant activity in the liver.

## Abstract

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.

•Microenvironment-adaptive nanocarrier enables targeted delivery and enhances therapeutic efficacy of poorly soluble flavonoids in acute liver injury.•The nanoparticle system synergistically scavenges ROS and inhibits ER stress-mediated calcium overload in hepatocytes.•Carrier–drug cooperation restores ER and mitochondrial redox balance, reducing hepatocyte apoptosis and liver injury.

Microenvironment-adaptive nanocarrier enables targeted delivery and enhances therapeutic efficacy of poorly soluble flavonoids in acute liver injury.

The nanoparticle system synergistically scavenges ROS and inhibits ER stress-mediated calcium overload in hepatocytes.

Carrier–drug cooperation restores ER and mitochondrial redox balance, reducing hepatocyte apoptosis and liver injury.