Biomimetic mineralized mesenchymal stem cell-derived exosomes for dual modulation of ferroptosis and lactic acid-driven inflammation in acute liver injury therapy

Abstract

Acute liver injury (ALI) is characterized by rapid and severe hepatocellular damage, leading to ferroptosis and an exacerbated inflammatory response. Mesenchymal stem cell-derived exosomes (MSC-exo) have emerged as a promising therapeutic strategy for ALI due to their ability to deliver antioxidants and stabilize solute carrier family 7 members 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) system. In this study, we developed a novel engineered exosome, MSC-exo/MnO₂@DEX, by encapsulating the anti-inflammatory drug dexamethasone (DEX) within MSC-exo and modifying its surface with manganese dioxide (MnO₂) via a bionano-mineralization approach. MnO₂ exhibits multi-enzymatic activity, enabling efficient scavenging of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anions. When combined with MSC-exo, MnO₂ not only reduces ROS levels and generates oxygen but also stabilizes the SLC7A11/GPX4 axis, thereby protecting hepatocytes from ferroptosis. Concurrently, DEX suppresses the nuclear factor-κB (NF-κB) signaling pathway, inhibits macrophage M1 polarization, and alleviates hepatic inflammation. The oxygen produced by MnO₂ catalysis further mitigates hypoxia, decreases lactic acid accumulation, and downregulates histone lactylation, synergizing with DEX to enhance NF-κB pathway inhibition and amplify anti-inflammatory effects. Transcriptomic analyses revealed that MSC-exo/MnO₂@DEX significantly enhances antioxidant capacity, metabolic processes, and immune function, while improving liver function and suppressing ferroptosis, lactylation and inflammatory responses. Collectively, these findings demonstrate the therapeutic potential of MSC-exo/MnO₂@DEX as an effective treatment for ALI.