2. Academic Validation
  3. Celastrol-loaded biomimetic nanodrug ameliorates APAP-induced liver injury through modulating macrophage polarization

Celastrol-loaded biomimetic nanodrug ameliorates APAP-induced liver injury through modulating macrophage polarization

  • J Mol Med (Berl). 2023 May 2. doi: 10.1007/s00109-023-02321-8.
Jing Zheng 1 2 3 4,  Ni Yang 1 2 3,  Yingying Wan 1 2 3,  Wenjing Cheng 1 2 3,  Gan Zhang 1 2 3,  Shi Yu 1 2 3,  Baoye Yang 1 2 3,  Xinyu Liu 1 2 3,  Xingyan Chen 5,  Xueliang Ding 1 3 6,  Ling Wu 7,  Xiang Yu 8 9 10
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China.
  • 2 Institute of Infection and Inflammation, China Three Gorges University, Yichang, China.
  • 3 Medical College, China Three Gorges University, Yichang, China.
  • 4 The People's Hospital of China Three Gorges University, Yichang, China.
  • 5 Tong Ji Hospital, Tongji Medical College of HUST, Wuhan, China.
  • 6 Department of Clinical Laboratory, Affiliated Renhe Hospital of China Three Gorges University, Yichang, China.
  • 7 The People's Hospital of China Three Gorges University, Yichang, China. [email protected].
  • 8 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China. [email protected].
  • 9 Institute of Infection and Inflammation, China Three Gorges University, Yichang, China. [email protected].
  • 10 Medical College, China Three Gorges University, Yichang, China. [email protected].
PMID: 37129620 DOI: 10.1007/s00109-023-02321-8
Abstract

Drug-induced liver injury (DILI) is a major concern in clinical treatment as well as postmarketing surveillance, showing an urgent requirement for the development of protective medications. Celastrol (Cel), a highly active natural product extracted from the roots of Tripterygium wilfordii, has a potential liver protective activity due to its antioxidant and anti-inflammatory effects. However, the further application of Cel to DILI remains a challenge because of its short half-life, low solubility, and toxic side effects. Herein, we developed a Cel-loaded biomimetic nanodrug based on erythrocyte membrane vesicles (EMV) for protecting the liver from acetaminophen (APAP)-induced liver injury. The Cel-loaded EMV (C-EMV) with lower cytotoxicity had a well-sustained release effect and exhibited excellent ability for liver accumulation under physiological and pathological conditions. By suppressing the inflammatory response of pro-inflammatory macrophage M1 polarization while stimulating anti-inflammatory macrophage M2 polarization, C-EMV could significantly alleviate the primary pathological manifestations related to liver injury, including aberrant elevation of biochemical indicators, histopathological alterations, neutrophil infiltration as well as hepatocyte DNA fragmentation. The macrophage depletion experiment further demonstrated that the protective effect of C-EMV on APAP-induced liver injury appeared to be dependent on hepatic macrophages. Therefore, C-EMV as a biomimetic nanodrug exhibits great potential for attenuating the progress of DILI, providing a new approach to protecting the liver from DILI as well as other liver inflammatory diseases through a targeted nanodelivery system. KEY MESSAGES: EMV biomimetic nanocarrier has good monodispersity and sustained-release property. EMV biomimetic nanocarrier displays excellent liver-targeting capability under physiological and pathological conditions. C-EMV biomimetic nanodrug with lower cytotoxicity regulates macrophage polarization in vitro and in vivo. C-EMV biomimetic nanodrug can significantly alleviate APAP-induced liver injury. The protective effect of C-EMV on APAP-induced liver injury is dependent on hepatic macrophages.

Keywords

Acetaminophen; Celastrol; Drug-induced liver injury; Macrophage polarization.

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