Chemically programmable hybrid membrane-camouflaged acetate gossypol prodrug reprograms the hepatic microenvironment for the treatment of liver fibrosis

Liver fibrosis represents a critical pathological process in chronic liver disease for which precision therapies remain limited. Here we report a biomimetic nanodrug (RAET NPs) that integrates a reactive oxygen species (ROS)-responsive prodrug of acetate gossypol with hybrid cell membrane camouflage and aptamer-mediated targeting. RAET NPs are constructed through modular assembly: the ROS-responsive prodrug core is encapsulated within a hybrid membrane shell formed by fusing activated hepatic stellate cell (HSC)-derived exosome membranes with M1-type macrophage membranes, followed by decoration with CD44-specific nucleic acid aptamers. This design preserves the full repertoire of membrane-associated targeting proteins while incorporating synthetic aptamers for enhanced recognition specificity. Meanwhile, RAET NPs remain in an inert state under normal physiological conditions to reduce biotoxicity and are converted into active drugs only in the fibrosis-induced reactive oxygen species (ROS)-rich microenvironment, enabling controlled drug release at the lesion site. In both organoid and animal models of liver fibrosis, RAET NPs suppress HSC activation and extracellular matrix deposition, significantly attenuating disease progression. This biomimetic nanomedicine offers a novel strategy for precision treatment of liver fibrosis through the synergistic function of prodrug and biomimetic delivery.