What question did this study set out to answer?

This research aims to develop a dexamethasone prodrug nanoparticle system that effectively treats liver fibrosis while minimizing systemic toxicity.

June 3, 2026Journal of Nanobiotechnology0 citationsOpen Access

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

ZZZhi ZhuBeijing University of Chinese Medicine JAJin AnBeijing University of Chinese Medicine ZZZijie ZhangJinggangshan University

Key Points

This research aims to develop a dexamethasone prodrug nanoparticle system that effectively treats liver fibrosis while minimizing systemic toxicity.
Developed GGT-responsive dexamethasone prodrug nanoparticles (DEI-NPs) for targeted liver delivery.
Evaluated the effects on hepatic stellate cell activation and intrahepatic immunity reprogramming.
Utilized TGF-β/Smad3 and TH17 pathways to assess fibrosis modulation.
DEI-NPs significantly reduced collagen I/IV deposition with an associated effect size (p<0.05).
TGF-β activation was suppressed, demonstrating a reduction in hepatic stellate cell activation (p<0.01).
Intrahepatic TH17/Treg rebalancing was achieved, indicating successful immunometabolic reprogramming.

Abstract

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.

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