Quadruplex Bioactive FAND for Treating Acute Liver Failure Induced by Acetaminophen or Hepatectomy

Acute liver failure (ALF), characterized by severe hepatocyte necrosis with a high mortality rate, remains a major global health challenge. However, there are currently no effective drug options for the clinical treatment of ALF. Herein, inspired by the new concept of a full-API nanodrug (FAND), we have rationally developed a quadruplex bioactive FAND (termed FAND^HP@FuEVs) composed entirely of active pharmaceutical ingredients (APIs). This FAND^HP@FuEVs is constructed from fusion extracellular vesicles (FuEVs), which hybridize M2 macrophage-derived EVs (M2–EVs) with mesenchymal stem cell-derived EVs (MSC-EVs) and is subsequently engineered with two clinically therapeutic biomacromolecules: hepatocyte growth factor (HGF) and polyene phosphatidylcholine (PPC). Notably, FAND^HP@FuEVs efficiently targets the damaged liver, benefiting from the dual inherent inflammation-tropism of the FuEVs. Moreover, FAND^HP@FuEVs harnesses quadruplex biological activities by leveraging four natural bioactive components—M2-EVs, MSC-EVs, HGF, and PPC—to deliver pleiotropic therapies, including antioxidant, anti-inflammatory, pro-regenerative, and macrophage repolarization effects. These therapies are effective in treating ALF induced by both acetaminophen and hepatectomy, demonstrating significant clinical relevance based on data from patients with liver disease. Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF.