CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Pengfei Yuan,Xiaodie Yan,Tianci Zhu,Xiaoqing Zong,Xinjie Chen,Caiqi Yang,Siying Wei,Yaoqi Wen,Jingru Du,Xiang Liu,Fengying Liu,Jian Dai
The epigenetic silencing of the cGAS-STING pathway in cancer cells significantly compromises tumor immune surveillance, posing a major challenge in immunotherapy. To address this, we developed an ionizable membrane fusion liposome system capable of transplanting STING protein-enriched endoplasmic reticulum (ER) directly into the cytosol of cancer cells, thereby reactivating the suppressed STING pathway. By modifying the liposomes with demethylcantharidin (DMC, an antitumor drug), the system maintains a neutral surface charge under physiological conditions, which enhances circulation stability and reduces hepatic clearance. In the mildly acidic tumor microenvironment, DMC cleavage induces a charge reversal, thereby restoring membrane fusion capability and facilitating tumor-specific accumulation. Reactivation of the STING pathway in tumor cells, combined with DMC-induced tumor antigen release, synergistically stimulates immune cell recruitment, effectively transforming immunologically “cold” tumors into “hot” tumors. This therapeutic strategy leverages endogenous organelle-derived biomaterials to restore cellular functions by directly delivering functional proteins and bioactive components into the cytosol. Altogether, our study provides a mechanistic rationale and therapeutic proof-of-concept for harnessing natural biological materials and their composites to enable innovative treatments for complex diseases.
研究领域:
肿瘤学
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免疫学
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生物材料
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
PHYTOTHERAPY RESEARCH
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2025
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IF 6.3
Lu Liu,Zhongxia Wang,Yulin Qi,Ang Huang,Caiping He,Xiaoyan Zhan,Xiaohe Xiao,Zhaofang Bai
Aberrant activation of the cGAS-STING pathway has been implicated in the pathogenesis of diverse inflammatory diseases. Kurarinone, a flavonoid compound isolated from Sophorae tonkinensis Radix et Rhizoma, has been reported to exhibit anti-inflammatory effects and is used to treat inflammatory diseases. But the effect of kurarinone on the cGAS-STING pathway has not been well studied. We aimed to investigate the impact of Kurarinone on cGAS-STING pathway activation and its protective effect against cGAS-STING-mediated inflammatory diseases. BMDMs and THP-1 cells pretreated with Kurarinone or vehicle were stimulated with ISD or various STING agonists; the protein level of p-IRF3 was analyzed by western blotting, and the secretion and mRNA level of inflammatory cytokines were detected by ELISA and qPCR, respectively. To further explore the potential targets and molecular mechanisms of Kurarinone, nucleocytoplasmic separation assays, STING oligomerization experiments, cellular thermal shift assays, drug affinity responsive target stability assays, and molecular docking were conducted. Additionally, DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models were used to evaluate the effects of Kurarinone on cGAS-STING-mediated inflammatory diseases. In vitro, Kurarinone inhibited the phosphorylation of STING and IRF3, reduced IFNβ release, and downregulated the transcription of IFNβ, IL-1β, CXCL10, IL-6, TNF-α, and ISG15, in ISD-stimulated BMDMs and THP-1 cells. Additionally, Kurarinone suppressed IRF3 nuclear translocation, disrupted the interaction between STING and IRF3, but did not affect STING oligomerization. Furthermore, Kurarinone reduced the thermostability of STING while increasing its susceptibility to proteolytic degradation. The molecular docking results indicated a strong interaction between Kurarinone and STING. In vivo, Kurarinone attenuated the inflammatory response in DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models by inhibiting cGAS-STING signaling activation. In conclusion, Kurarinone targets the STING protein to interfere with the interaction between IRF3 and STING, thereby inhibiting the activation of the cGAS-STING signaling pathway. Additionally, Kurarinone ameliorates inflammatory diseases by suppressing the cGAS-STING pathway. This study provides a potential candidate drug for the clinical treatment of STING-driven inflammatory diseases.
研究领域:
免疫学
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分子生物学
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药理学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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