Iridium Nanoantidotes Attenuate Jellyfish Toxin-Induced Hepatotoxicity by Inhibiting Gasdermin D Palmitoylation.

Jellyfish envenomation poses a significant clinical challenge, with Nemopilema nomurai (N. nomurai) venom capable of inducing life-threatening hepatotoxicity through mechanisms that remain poorly understood. Here, we demonstrate that its tentacle extract (TE) simultaneously triggers a reactive oxygen species (ROS) burst, activates the canonical NLRP3/Caspase-1/Gasdermin D (GSDMD) pyroptosis pathway, and induces ZDHHC9-dependent GSDMD palmitoylation, collectively contributing to hepatic injury. To counteract this dual-pathway activation, we engineered ultrasmall iridium nanoantidotes (Ir NAs) with multienzyme mimetic activities, which effectively scavenge ROS, thereby suppressing both NLRP3 inflammasome activation and GSDMD palmitoylation while preserving mitochondrial function. These nanoantidotes significantly attenuated hepatocyte pyroptosis and histopathological damage, reduced mortality in vivo, and exhibited favorable biocompatibility with rapid clearance. Our work not only identifies GSDMD palmitoylation as a critical event in jellyfish venom-induced hepatotoxicity but also presents a translatable nanotherapeutic strategy for marine envenomation and related inflammatory disorders.