Fully Bioactive\nNanodrugs: Stem Cell-Derived Exosomes\nEngineered with Biomacromolecules to Treat CCl<sub>4</sub>- and Extreme\nHepatectomy-Induced Acute Liver Failure

Acute liver failure (ALF) is a serious global disease\ncharacterized\nby rapid onset and high mortality. Currently, the clinical treatment\nof ALF faces considerable hurdles due to limited medication options\nand the scarcity of liver transplants. Despite biomacromolecules such\nas hepatocyte growth factor (HGF) and glutathione (GSH) having been\napplied for ALF symptom relief in the clinic, they still face substantial\nchallenges including poor stability, difficulty in acting on intracellular\ntargets, and inadequate therapeutic outcome. In this work, by taking\nadvantage of the innate targeting and regenerative capabilities of\nmesenchymal stem cells (MSCs), we harnessed MSC-derived exosomes as\nnatural bioactive carriers for the simultaneous delivery of HGF and\nGSH, forming a fully bioactive nanodrug termed HG@Exo. Impressively,\nthe HG@Exo demonstrated potent therapeutic effects against both carbon\ntetrachloride (CCl<sub>4</sub>)- and extreme hepatectomy-induced ALF\nthrough multiple mechanisms, including regulation of oxidative stress,\nreduction of inflammation, and promotion of hepatocyte regeneration,\nwhich were facilitated by its inflammation-targeting to damaged liver\ntissues. Furthermore, an FDA-approved near-infrared fluorescent dye,\nindocyanine green (ICG), has been incorporated into the exosomes (HGI@Exo)\nto endow them with real-time <i>in vivo</i> tracking capability,\nwhich showed favorable liver accumulation of the HGI@Exo in both CCl<sub>4</sub>- and surgery-induced ALF animal models, providing crucial\ninsights into their biodistribution and therapeutic efficacy. Overall,\nthe presented fully bioactive nanodrugs with targeting and theranostic\nabilities hold significant promise for potentiating the therapeutic\nefficacy of biomacromolecules for the improved treatment of ALF and\nother inflammatory diseases.