Nanotherapy based on mesenchymal stem cell-derived extracellular vesicles target ADAM17-mediated TREM2 shedding on macrophages to promote efferocytosis for acute liver failure treatment

Acute liver failure (ALF) is a life-threatening condition characterized by extremely high mortality and the absence of effective therapies. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) constitute a promising cell-free nanotherapeutic approach for ALF, yet their underlying mechanisms remain to be fully elucidated. Recent studies indicate that the efferocytosis function of macrophages is crucial for the clearance of apoptotic cells, resolution of inflammation, and subsequent tissue repair during ALF. In this study, we found that adipose-derived MSC-EVs (AMSC-EVs) effectively restored macrophage efferocytosis and thereby facilitated inflammatory resolution and mitigated liver injury in Lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF. We further identified that TREM2 as a critical mediator of this therapeutic effect. Firstly, AMSC-EVs could prevent the reduction of full-length TREM2 level in mouse liver tissue after LPS/D-GalN-challenge, as well as the decrease of TREM2 on macrophages membrane after LPS stimulation. Secondly, they conferred no significant improvement in efferocytosis in TREM2 ⁻/⁻ macrophages and failed to rescue ALF in myeloid-specific TREM2-deficient mice. Mechanistically, AMSC-EVs suppressed ADAM17-mediated TREM2 cleavage by downregulating p65-dependent ADAM17 transcription through miR-145-5p, thereby restoring the efferocytosis function of macrophages and then enhancing efferocytosis-mediated secretion of anti-inflammatory and pro-resolving cytokines to prevent necrosis and inflammation and activate resolution in ALF. Our findings uncover the therapeutic mechanism of AMSC-EVs in targeting macrophage dysfunction in ALF and the potential of AMSC-EVs as nanotherapies for defective efferocytosis-related diseases.