Fluorinated Proteolysis Targeting Chimeras-Sorafenib Nanoassembly for Epigenetic Remodeling to Combat Multi-Pathway Drug Resistance in Hepatocellular Carcinoma

  • ACS Nano. 2025 Oct 7;19(39):34659-34676. doi: 10.1021/acsnano.5c08326.
Taian Lin  1 ,  Yixuan Hou  1 ,  Xueqing Liu  2 ,  Ihsan Ullah  1 ,  Siyu Qiu  3 ,  Zidong Lu  3 ,  Jianyong Qi  2 ,  Youyong Yuan  1  4  5
Affiliations
  • 1. School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 511442, P. R. China.
  • 2. Intensive Care Research Team of Traditional Chinese Medicine, Guangdong Province Academy of Chinese Medicine, Guangzhou 510006, P. R. China.
  • 3. School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.
  • 4. National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China.
  • 5. Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, P. R. China.
PMID: 40977536 DOI: 10.1021/acsnano.5c08326
Abstract

Although sorafenib (SF) is the standard first-line therapy for hepatocellular carcinoma (HCC), extended exposure frequently induces multipathway resistance driven by tumor hypoxia and an immunosuppressive microenvironment. Here we report a fluorinated Proteolysis TArgeting Chimeras (PROTAC)-sorafenib nanoassembly (FCP@SF/FPro) that boosts efficacy by degrading bromodomain-containing protein 4 (BRD4) and rewiring epigenetic programmes. This innovative system integrates fluorinated PROTAC targeting BRD4 (FPro) and sorafenib within a fluorinated poly(ethylene glycol)-conjugated poly(ethylenimine) (FCP) matrix, stabilized by fluorine-fluorine and hydrophobic interactions, ensuring high drug encapsulation efficiency and stability. By swiftly degrading BRD4, FCP@SF/FPro triggers Apoptosis, down-regulates hypoxia-inducible factor 1-α (HIF-1α) to blunt hypoxia signaling, and relieves immunosuppression by lowering programmed death-ligand 1 (PD-L1) while boosting the M1/M2 tumor-associated macrophages (TAMs) ratio. The dual-payload platform suppresses tumors by coupling BRD4 degradation-driven epigenetic rewiring with immune-checkpoint relief. In vitro and in vivo, FCP@SF/FPro potently inhibits HCC growth and metastasis, highlighting its innovative potential as a fluorinated PROTAC-sorafenib combination therapy for drug-resistant HCC.

Keywords
epigenetic remodeling; hepatocellular carcinoma; multipathway drug resistance; proteolysis targeting chimeras; tumor immunosuppressive microenvironment.
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