Cross-Linked Lipoic Acid Trisulfide Nanoparticles against Acute Liver Injury by Multipathway Regulation

Acute liver injury (ALI) poses a severe treatment challenge due to multipathological mechanisms. Herein, cross-linked lipoic acid trisulfide nanoparticles (cLAT NPs) were developed against ALI by self-assembly and ring-opening polymerization of lipoic acid trisulfide (LAT). Upon accumulation in the liver, the cLAT NPs, owing to the polysulfide structure, highly efficiently entered into cells via thiol-mediated uptake and generated hydrogen sulfide (H 2 S) by intracellular glutathione (GSH)-responsive depolymerization. Concurrently, the highly biocompatible compound lipoic acid (LA) was produced, which promoted the expression of endogenous H 2 S-producing enzymes, such as cystathionine γ-lyase (CSE), thereby augmenting the endogenous H 2 S generation. Ultimately, cLAT NPs exerted hepatoprotective effects through multipathway regulation, including direct scavenging of reactive oxygen species (ROS), activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibition of nuclear factor kappa-B (NF-κB). Notably, a single intravenous administration of 10 mg/kg cLAT NPs ultimately achieved a 100% survival rate in the ALI mouse model, whereas the clinical drug N-acetylcysteine (150 mg/kg) yielded only a 20% survival rate. cLAT NPs provide a paradigm against ALI by multipathway regulation.