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<p>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 <i>via</i> dual pathways. DEI-NPs could suppress hepatic stellate cell activation <i>via</i> 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月1日

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  • Zhi Zhu,
  • Jin An,
  • Zijie Zhang,
  • Feng Gao,
  • Dongling Liao,
  • Jie Wang,
  • Huoli Yin,
  • Xinran Huang,
  • Kaixuan Kang,
  • Yongji Liu,
  • Xingchen Duan,
  • Bing Xu,
  • Haimin Lei

摘要

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.

Graphical Abstract