Mannose-modified multifunctional iron-based nanozyme for hepatocellular carcinoma treatment by remodeling the tumor...

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with conventional treatments often accompanied by severe side effects. Recently, nanozymes have been extensively employed in cancer therapy due to their enhanced enzymatic activities, stability compared to native enzymes. However, a standalone nanozyme exhibits insufficient targeting capability and fails to specifically localize to the pathological site. In this study, we successfully synthesized a multifunctional iron-based-nanozyme delivery system - Fe₃O₄-OA-DHCA-PEI-MAN@DSF modified with PEI and MAN by the thermal decomposition method. This mannose-modified nanozyme can specifically target HCC cells via an external magnetic field and mannose-mannose receptor (MRC2) binding. In addition, it exhibits good biocompatibility and pH-dependent drug release characteristics. Within the acidic tumor microenvironment, the iron-based nanozyme initiates intracellular fenton reactions, boosting reactive oxygen species (ROS) production, which ultimately induces apoptosis in HCC cells. Concurrently, the disulfiram small molecule released from the Fe₃O₄-OA-DHCA-PEI-MAN@DSF nanozyme binds to the FROUNT factor within monocyte-macrophages, thereby inhibiting their response to chemotactic signals emitted by liver cancer cells. This process ultimately suppresses the recruitment of macrophages by HCC cells, reshaping the tumor microenvironment and supporting effective liver cancer treatment. Moreover, this nanozyme system holds potential for MRI-guided targeted chemotherapy combined with chemodynamic therapy, aiming to refine the early diagnosis and precision treatment of hepatic carcinoma, and paving the way for the creation of sophisticated integrated nanoplatforms melding diagnostic and therapeutic functionalities.