An all-in-one theranostic platform for enhanced TACE: self-developing embolization with dual-targeted arsenic trioxide delivery

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality. For patients with advanced, unresectable disease, transarterial chemoembolization (TACE) is a recommended first-line locoregional therapy. However, its efficacy is constrained by the inherent limitations of conventional embolic materials-such as non-target embolization, vessel recanalization, and incomplete distal occlusion-and by the low intra-tumoral delivery efficiency of chemotherapeutic agents. Furthermore, the high prevalence of p53 mutations (~ 30%) in HCC drives tumorigenesis and chemoresistance, creating a critical therapeutic gap, especially within the hypoxic tumor microenvironment. To address these multifaceted challenges, we developed an innovative theranostic platform, CHSA/NAT. This system combines a radiopaque, thermosensitive hydrogel (NAT) for precise, image-guided vascular occlusion with CD44-targeted, glutathione (GSH)-responsive chitosan/hyaluronic acid nanomicelles (CHSA), which enable the smart delivery of arsenic trioxide (ATO)-a potent agent with p53-mutant corrective activity. In vitro, ATO demonstrated superior cytotoxicity over doxorubicin against multiple HCC cells under hypoxia. In a p53-mutant PLC/PRF/5 subcutaneous model, CHSA-ATO achieved a tumor inhibition rate of 84.6%, significantly outperforming free ATO and doxorubicin, and effectively modulated apoptotic proteins (downregulating mutant p53/Bcl-2, upregulating Bax). Crucially, superselective administration of CHSA/NAT enabled successful embolization with clear radiological visualization in rat hepatic and renal arteries, demonstrating its precise image‑guided delivery and embolization capability. Most importantly, in an orthotopic rat HCC model, the combined treatment exhibited powerful synergistic efficacy, attaining a remarkable 96% tumor suppression rate and significantly prolonging survival, with a favorable safety profile. This work presents a novel "embolization‑imaging‑targeted chemotherapy" strategy that simultaneously overcomes the key limitations of conventional TACE and ATO delivery, offering a promising and translatable nanoplatform for the effective treatment of advanced HCC.