CXCR4-targeted dual softener for inducing senescence therapy in hepatic fibrosis

Hepatic fibrosis is a central pathological driver of chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, which collectively impose a growing global health burden. Fibrosis is primarily mediated by persistent activation of hepatic stellate cells (aHSCs) and excessive deposition of stiff extracellular matrix (ECM). The dense and rigid ECM-aHSCs network severely hinders drug delivery and penetration, posing a major challenge for effective antifibrotic therapy. Here, we developed an aHSCs-targeted nanocomplex (AMD3100/MnO₂@BSA nanoparticles, AMB NPs) to remodel this rigid fibrotic barrier. This platform inhibits the fibrotic process by inducing cellular senescence and activating endogenous immune surveillance. Upon liver accumulation, AMB NPs preferentially recognize CXCR4 on aHSCs and subsequently release Mn²⁺ to engage the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune pathway, thereby robustly inducing cellular senescence, suppressing cell proliferation and reducing cellular stiffness. This process enhances the production of senescence-associated secretory phenotype factors, promotes collagen degradation and matrix loosening, and facilitates immune-mediated clearance of senescent aHSCs. These findings demonstrate the potent antifibrotic efficacy of AMB NPs and highlight a synergistic nanomedicine strategy that integrates aHSCs senescence induction, immune surveillance, and ECM remodeling, providing a rational therapeutic framework for hepatic fibrosis intervention.