GGT-triggered self-immolative dexamethasone-oligopeptide prodrug nanoparticles ameliorate hepatic fibrosis via dual anti-inflammatory/immunomodulatory pathways with minimized systemic toxicity.

Liver fibrosis remains a critical unmet medical challenge, where glucocorticoids' therapeutic potential is constrained by systemic toxicity. We innovatively address this through an amphiphilic prodrug (DEI) engineered by Michael addition-conjugating dexamethasone with I-C-F-6, which self-assembles into γ-glutamyltranspeptidase (GGT)-responsive nanoparticles for liver-targeted delivery. This nanoplatform achieves spatial precision through enzyme-triggered drug self-immolative release exclusively in fibrotic livers, minimizes systemic toxicity, and modulates fibrosis pathogenesis via dual pathways. DEI-NPs could suppress hepatic stellate cell activation via TGF-β/Smad3 and TH17 pathway blockade to halt collagen I/IV deposition, and reprogram intrahepatic immunity through retinol metabolism-mediated TH17/Treg rebalancing (Cyp2a1↓/STAT1↑). Our work pioneers a paradigm-shifting strategy in glucocorticoid therapy that merges GGT-activated spatial control with immunometabolic reprogramming, effectively overcoming critical bottlenecks in fibrosis therapy.