At the 2024 American Association for the Study of Liver Diseases (AASLD) Annual Meeting, Professor Mingqin Lu’s team from The First Affiliated Hospital of Wenzhou Medical University unveiled their latest research breakthrough: biomimetic exosomes derived from endotoxin-tolerant dendritic cells (ETDC-EM) loaded with iridium nanozyme (Ir NPs-PVP) for the treatment of acute liver failure (ALF). The study demonstrated that by constructing exosome mimics (EMs) derived from ETDCs and loading them with iridium nanozyme, which possesses catalase (CAT) and peroxidase (POD)-like activities, the therapeutic efficiency was significantly enhanced. In a mouse model of ALF, ETDC-EM/Ir NPs-PVP exhibited notable anti-inflammatory and antioxidative effects, effectively mitigating liver pathology and extending survival. This innovative therapy provides a promising new approach for ALF treatment, with potential to substantially improve patient outcomes.Acute liver failure (ALF) is a severe clinical syndrome characterized by the rapid deterioration of liver function, often accompanied by multi-organ failure. Given its complex mechanisms and limited treatment options, innovative therapeutic approaches are urgently needed. Dendritic cells (DCs) play a crucial role in bridging innate and adaptive immunity, with endotoxin-tolerant dendritic cells (ETDCs) exhibiting significant anti-inflammatory properties. However, the instability of ETDCs has hindered their direct use in vivo. To address this, researchers designed biomimetic exosome mimics (ETDC-EM) derived from ETDCs and loaded them with polyvinylpyrrolidone-stabilized iridium nanoparticles (Ir NPs-PVP) for their antioxidative effects.
In this study, bone marrow-derived dendritic cells (BMDCs) were extracted from mice and transformed into ETDCs through a specific LPS stimulation protocol. Ir NPs-PVP, synthesized via an ethanol thermal reduction method, were characterized and subsequently loaded into ETDC-EM. The therapeutic efficacy of the resulting ETDC-EM/Ir NPs-PVP complex was evaluated in a mouse model of ALF.
Flow cytometry confirmed the purity of BMDCs, and optical microscopy revealed that ETDCs resembled unstimulated BMDCs. The Ir NPs-PVP particles were found to have a sub-spherical structure with an average diameter of approximately 1.75 nm and a zeta potential of -15.4 mV. The ETDC-EM and ETDC-EM/Ir NPs-PVP both exhibited intact spherical membrane structures, with the latter displaying black granules inside due to the presence of Ir NPs-PVP.
The antioxidative properties of Ir NPs-PVP were evaluated, with results showing a concentration-dependent increase in hydrogen peroxide (H2O2) removal. At a concentration of 200 μg/mL, Ir NPs-PVP achieved approximately 99% clearance of H2O2, demonstrating robust catalase (CAT)-like activity. Additionally, Ir NPs-PVP exhibited peroxidase (POD)-like activity, which increased with higher H2O2 concentrations. Flow cytometry and ESR spectra further confirmed Ir NPs-PVP’s ability to scavenge intracellular reactive oxygen species (ROS) and eliminate hydroxyl radicals (•OH).
The anti-inflammatory effects of ETDC-EM were assessed using LPS-stimulated RAW264.7 cells. ELISA data revealed that ETDC-EM significantly reduced the secretion of inflammatory cytokines TNF-α and IL-1β. Furthermore, CD86 expression in these cells decreased from 80.9% to 33.1% with ETDC-EM treatment.
ICP-MS analysis showed that ETDCs could encapsulate Ir NPs-PVP, achieving a loading rate of 10%. Metabolism studies indicated that Ir NPs-PVP metabolized rapidly in the liver, while ETDC-EM/Ir NPs-PVP exhibited more gradual metabolism. Multimodal optical imaging revealed that both ETDC-EM and ETDC-EM/Ir NPs-PVP accumulated in the liver, with the latter aggregating faster.
Safety assessments showed no significant damage to major organs or cytotoxicity to RAW264.7 cells. Hemolysis tests confirmed a low hemolysis rate at the highest therapeutic concentration of ETDC-EM/Ir NPs-PVP.
In the ALF mouse model, ETDC-EM/Ir NPs-PVP treatment significantly alleviated pathological liver changes, reduced inflammation-induced liver damage, and decreased serum levels of inflammatory cytokines and liver enzymes. Survival curves demonstrated that the treatment effectively extended the survival time of ALF mice. DHE staining of liver tissues confirmed the suppression of ROS levels after treatment, highlighting the antioxidative protective effects of Ir NPs-PVP.
In conclusion, this study successfully developed a novel therapeutic approach for ALF using ETDC-EM/Ir NPs-PVP. The complex exhibited robust anti-inflammatory and antioxidative capabilities, effectively mitigating liver inflammation and providing hepatoprotective effects in the ALF mouse model. This innovative approach offers a promising new avenue for the clinical treatment of ALF.
