Dual-scaffold imageable embolic system with microenvironment normalization enhances hypoxia-activated chemoembolization for HCC

Transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is limited by the post-embolization tumor microenvironment (pE-TME), which drives revascularization and fibrosis, thereby narrowing the hypoxic window and restricting drug penetration for hypoxia-activated prodrugs like tirapazamine (TPZ). To overcome this challenge, we developed a dual-scaffold theranostic platform integrating an iodinated thermosensitive PNIPAM hydrogel with genipin-crosslinked albumin microspheres for the coordinated co-delivery of nintedanib (NIB) and TPZ. This platform provides intrinsic X-ray visibility, rapid in situ gelation, enhanced mechanical strength, and sustained drug release with excellent hemocompatibility. In vitro, released NIB inhibited fibroblast proliferation, while TPZ potently induced apoptosis in hypoxic HCC cells. In vivo, the platform enabled stable vascular occlusion and prolonged tumor retention. In an orthotopic HCC model, the dual-drug combination achieved 91% tumor inhibition, significantly outperforming embolization alone and single-drug groups, without systemic toxicity. Mechanistically, TPZ promoted apoptosis (Caspase-3/Ki-67), whereas NIB suppressed compensatory angiogenesis (VEGF/CD31) and collagen deposition (α-SMA), thereby remodeling the pE-TME to stabilize hypoxia. By converting the therapy-limiting hypoxic microenvironment into a therapeutic asset, this dual-scaffold strategy offers a new paradigm for amplifying TACE efficacy.