Hierarchical embolization integrating hypoxia modulation and immune reprogramming for enhanced hepatocellular carcinoma therapy.

Transarterial embolization (TAE) remains a primary treatment option for advanced hepatocellular carcinoma, but its efficacy is often compromised by incomplete vascular occlusion and treatment resistance caused by hypoxia. Conventional embolic agents suffer from poor distal embolization due to particle-vessel size mismatch, while the resulting hypoxia microenvironment aggravates chemoresistance and fosters immune-suppression. To overcome these challenges, we developed a hierarchical embolization system based on the mSiO2/Pt/aPD-1@HAMA microspheres that synergistically enhance vascular occlusion and therapeutic response. In this system, hyaluronic acid methacryloyl (HAMA) microspheres achieve the proximal arterial embolization, whereas mesoporous silica (mSiO2) particles embedded within the HAMA matrix are sized to correspond to vessels of capillary caliber and are designed to achieve secondary microvascular occlusion after release, with the aim of establishing a multi-level hierarchical vascular embolization. In addition, the Pt nanoparticles loaded in mSiO2 catalyze the decomposition of tumor-overexpressed H2O2 into O2, partially alleviating hypoxia and disrupting resistance mechanisms within the tumor microenvironment. Importantly, instead of conventional cytotoxic chemotherapy in transcatheter arterial chemoembolization (TACE), this hierarchical embolic system incorporates anti-PD-1 (aPD-1) antibodies within the mesoporous channels of mSiO2, thereby directing the local therapeutic action toward immune activation. Synergistically, the oxygen-enriched microenvironment induced by Pt-catalysis further augments the immune checkpoint blockade by reversing local immunosuppression and restoring T cell function. In a preclinical rabbit VX2 tumor model, this hierarchical embolization strategy achieved markedly enhanced anti-tumor effect compared with standard embolic agents. Collectively, these findings provide proof-of-concept evidence for an embolization strategy integrating hierarchical vascular occlusion, hypoxia modulation, and immune checkpoint blockade.