Integrated Microneedle Patches Combining PROTAC-Derived Phytochemicals, Ceria Nanozymes, and Puerarin Hydrogels for Targeted Treatment of Acetaminophen-Induced Acute Liver Injury

Abstract Acute liver failure (ALF) is a critical clinical condition associated with rapid deterioration and substantial mortality, in which dysregulated crosstalk between oxidative stress and inflammatory cascades plays a pivotal pathogenic role. However, current therapeutic strategies remain inadequate due to the pharmacokinetic barrier of achieving efficient hepatic drug accumulation. Herein, we report a multifunctional microneedle-based therapeutic platform (MN(PUE)−Hed#3/CeO2) for precise hepatic delivery and spatiotemporal modulation of the oxidative stress−inflammation axis in ALF management. Through rational PROTAC-mediated structural optimization of hederagenin, a novel proteolysis-targeting chimera (Hed#3) was developed, which retains the intrinsic antioxidant activity of the parent compound while exhibiting enhanced protein degradation efficiency, thereby amplifying cytoprotective effects. Integration with cerium oxide nanozymes yielded a Hed#3/CeO2@PLGA nanocomposite that synergistically couples molecular antioxidation with enzymatic reactive oxygen species (ROS) scavenging. Leveraging the thermoresponsive sol−gel transition and inherent anti-inflammatory activity of puerarin (PUE), this hybrid system was incorporated into a dissolvable microneedle array for localized and controlled hepatic drug release. Comprehensive pharmacodynamic studies demonstrated that MN(PUE)−Hed#3/CeO2 markedly attenuated acetaminophen-induced hepatotoxicity via concurrent activation of the Nrf2/HO-1 antioxidant defense pathway and inhibition of NF-κB−mediated proinflammatory signaling. This work establishes a therapeutically viable and translatable strategy for ALF treatment and presents a conceptual paradigm for targeted intervention of oxidative stress−associated inflammatory diseases.