Eosinophil-derived apoptotic extracellular vesicles accelerate steatotic liver repair after ischemia/reperfusion injury through mitochondria-associated metabolic reprogramming

Eosinophils have recently been recognized as hepatoprotective immune cells; however, cell-based therapies still face significant challenges. Apoptotic extracellular vesicles (ApoEVs) serve as critical cell-free alternatives capable of promoting tissue repair, yet exhibit marked functional heterogeneity dependent on their cell source. The therapeutic potential and mechanisms of eosinophil-derived ApoEVs (Eos-ApoEVs) in steatotic liver ischemia/reperfusion (I/R) injury remain elusive. Herein, treatment with Eos-ApoEVs effectively reversed oxygen–glucose deprivation/reperfusion (OGD/R)-induced cellular dysfunction in hepatocytes and liver sinusoidal endothelial cells (LSECs). Moreover, Eos-ApoEVs exerted potent immunomodulatory effects. Mechanistically, Eos-ApoEVs are enriched with functional mitochondria that fuse with damaged mitochondria in recipient cells, thereby reprogramming energy metabolism to promote hepatocyte proliferation, restore LSEC migration and tube-forming capacity, and facilitate anti-inflammatory macrophage polarization. To develop a clinically translatable therapeutic approach, we constructed a decellularized amniotic matrix (dAM)-based hydrogel patch (ApoEVs@dAM/HA-DA), which enables sustained release of ApoEVs and exhibits high biocompatibility. In a mouse model of steatotic liver I/R injury, transplantation of ApoEVs@dAM/HA-DA onto the liver surface significantly increased anti-inflammatory macrophage polarization, attenuated inflammation, promoted hepatocyte proliferation and enhanced angiogenesis, thereby accelerating liver repair. Thus, surface transplantation of ApoEVs@dAM/HA-DA provides a clinically viable and potent therapeutic strategy for steatotic liver I/R injury.