Metal-drug coordinated nanozymes for ROS scavenging and Kupffer cell polarization to alleviate drug-induced liver injury

Drug-induced liver injury (DILI) is a predominant cause of acute liver failure, intricately associated with excessive reactive oxygen species (ROS) production and the activation of inflammatory cascades. In this study, a metal–drug coordinated nanozyme (M-dCNs) is rationally designed to simultaneously scavenge ROS and polarize Kupffer cells to alleviate DILI. Specifically, the coordination between ferric ions (Fe 3+ ) and the complementary therapeutic agents of hesperetin (HST) and KPLH (KPLH1130) facilitates the formation of M-dCNs with uniform particle distribution and enhances structural stability. Notably, M-dCNs exhibits intrinsic antioxidant enzyme-mimetic activity, efficiently neutralizing intracellular ROS in damaged hepatocytes and thereby disrupting apoptosis-related signaling pathways. In parallel, M-dCNs synergistically reprograms hepatic macrophages toward an anti-inflammatory phenotype, leading to a marked reduction in pro-inflammatory cytokines such as tumor necrosis factor α (TNF- α ) and interleukin 1 β (IL-1 β ), and ultimately suppressing inflammatory cascades. In vivo studies demonstrate the hepatoprotective potential and therapeutic efficacy of M-dCNs in attenuating oxidative stress, reducing inflammatory cell infiltration, and restoring liver function. Collectively, this work presents a promising strategy for the treatment of DILI via the concurrent modulation of redox homeostasis and inflammatory microenvironment.