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

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. <i>In vitro</i> and <i>in vivo</i>, FCP@SF/FPro potently inhibits HCC growth and metastasis, highlighting its innovative potential as a fluorinated PROTAC-sorafenib combination therapy for drug-resistant HCC.