Abstract

Utilizing fusogenic systems for antioxidant delivery holds promise in treating acute liver injury (ALI), as it bypasses lysosomal degradation. However, conventional fusogenic nanocarriers often fuse non-specifically with unintended cells, causing off-target effects. To address this, we developed a reactive‑oxygen-species (ROS)-unlocking fusogenic liposome (RunFul) for spatially selective cytoplasmic antioxidant delivery. “Locked” by a PEG- b -PPBA polymer shell, RunFul remains stable in circulation and non-fusing with normal cells. In ALI sites, excess H 2 O 2 triggers the traceless detachment of polymer shell, “unlocking” the underlying fusogenic liposome for direct cytoplasmic delivery via membrane fusion, circumventing lysosomes. More importantly, this “unlocking” process also depletes H 2 O 2 species, achieving a dually-synergistic therapeutic effect. Loaded with a silymarin-Mn 2+ complex (SilMn), the nano-antioxidant (RunFul SilMn ) was demonstrated with superior therapeutic efficacy in a CCl 4 -induced ALI mouse model by alleviating oxidative damage, reducing inflammation, and promoting regeneration. This work presents a strategy of regulating membrane-fusion effect of fusogenic systems, providing a potent and synergistic delivery platform for ALI therapy.