Degradable Multifunctional Microspheres for Combined Thermotherapy‐Embolization‐Immune Activation Therapy of Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate and advanced hepatocellular carcinoma (HCC). Nevertheless, the upregulation of vascular endothelial growth factor A (VEGF-A) and the angiogenesis response triggered by the hypoxic environment following embolization can facilitate tumor recurrence. The combination of TAE/TACE and anti-angiogenic drugs has become one of the important strategies in the treatment of liver cancer. However, anti-angiogenic strategies using monotherapies that only target VEGF or vascular endothelial growth factor receptor (VEGFR) have limited efficacy in the treatment of HCC. Hence, we designed a degradable embolic microsphere (RegFe@MS) capable of simultaneously loading hydrophobic regorafenib and magnetic iron oxide nanoparticles. Through the "two-liquid phase sequential drug loading technology", RegFe@MS can effectively absorb and encapsulate regorafenib like a sponge. It has been shown that RegFe@MS can inhibit the upregulation of HIF-1α and the expression of CCR6 through mild hyperthermia, thereby suppressing the release of VEGF-A. In addition, local sustained release of regorafenib can be used to inhibit VEGFR. This strategy can not only inhibit the post-embolization angiogenic response but also maximally suppress the proliferation and invasion of residual tumors. Furthermore, RegFe@MS has demonstrated remarkable therapeutic effects in the rabbit orthotopic liver cancer model.