OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with features such as high recurrence, easy metastasis, and poor prognosis, posing significant challenges for clinical treatment. In this study, we introduce a novel approach for treating HCC using tumor cell-derived microparticles (MPs) co-loaded with sorafenib and gold nanoparticles (AuNP) in combination with radiotherapy. METHODS: MPSF@AuNP was prepared by co-incubating AuNP with sorafenib, and was evaluated using dynamic light scattering (DLS), transmission electron microscopy (TEM), ultraviolet-visible spectrophotometry (UV-Vis), inductively coupled plasma optical emission spectrometry (ICP-OES), high-performance liquid chromatography (HPLC), and SDS-PAGE electrophoresis. Subsequently, their targeting ability toward hepatocellular carcinoma cells and their combined antitumor therapeutic effects with radiotherapy were investigated through in vitro and in vivo experiments, while their in vivo safety was also assessed. RESULTS: Our results demonstrate that co-loaded microparticles (MPSF@AuNP) can effectively deliver therapeutic agents to tumor cells through homologous targeting, improving the bioavailability of therapeutic drugs and enhancing their cytotoxicity against tumor cells. Furthermore, the combination of MPSF@AuNP with radiotherapy shows a synergistic anti-tumor effect by enhancing the inhibition of tumor cell proliferation, promoting tumor cell apoptosis, remodeling the tumor microenvironment, and activating the anti-tumor immune responses. CONCLUSION: This study offers a promising treatment approach for malignant tumors such as HCC by using MP co-loaded and delivered with anti-tumor drugs and AuNP in combination with radiotherapy.