Effective treatment of orthotopic liver cancer with bifunctional embolization microspheres.

Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure used widely for the treatment of unresectable hepatocellular carcinoma (HCC). However, embolization-induced hypoxia upregulates VEGF, and the resulting angiogenic response contributes to tumor recurrence, further limiting the efficacy of TACE against HCC. Herein, we present a multifunctional embolic microsphere system in which sorafenib (SRF) and calcium carbonate (CaCO₃) nanoparticles are rationally encapsulated within sodium hyaluronate microspheres (SRF-CaCO₃@SH MSs) via microfluidic technology. The microspheres exhibited a bowl-shaped morphology with tunable diameters, which enhances in vivo embolic stability through mechanical interlocking between adjacent microspheres. In an acidic tumor microenvironment (TME), pH-triggered release of Ca²⁺ (23.9%) and SRF (65.7%) far exceeded neutral conditions. SRF-CaCO₃@SH MSs maintained >85% HUVEC viability and reduced VX2 cell viability to 24.3%, showing maximal cytotoxicity under acidic conditions. After intra-arterial injection, the microspheres occluded tumor-feeding arteries; Ca²⁺ released in the acidic TME inhibited angiogenesis, and CaCO₃ neutralized TME acidity, counteracting immunosuppression. In a rabbit VX2 orthotopic HCC model, DSA-guided TACE achieved effective occlusion, slowest tumor growth, largest necrosis, and marked downregulation of CD31, Ki67, and VEGF, without systemic toxicity. Combining morphological design, pH-responsive occlusion, TME neutralization, and anti-angiogenesis, this embolic system synergistically enhances TACE and shows strong clinical potential. STATEMENT OF SIGNIFICANCE: Conventional liver cancer embolization frequently fails due to hypoxia-driven angiogenesis and subsequent tumor recurrence. We developed a dual-functional embolic microsphere (SRF-CaCO₃@SH MS) that integrates stable vascular occlusion with active modulation of the tumor microenvironment. Utilizing microfluidics, we fabricated bowl-shaped sodium hyaluronate microspheres that mechanically interlock to ensure durable embolization. Under acidic tumor conditions, calcium carbonate neutralizes pH and releases Ca²⁺, which synergizes with sorafenib to inhibit angiogenesis and induce apoptosis. In a rabbit orthotopic HCC model, this system demonstrated superior tumor control and necrosis without inducing systemic toxicity. This work presents a microenvironment-responsive embolization strategy integrating durable vascular occlusion, pH modulation, and anti-angiogenic therapy.