Agarose-Encapsulated Multifunctional Microspheres with High Drug Payload and Multimodal Imaging Capability for...

Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related mortality worldwide, and transarterial chemoembolization (TACE) remains the standard first-line locoregional therapy for intermediate-stage HCC. Nevertheless, conventional TACE frequently yields suboptimal therapeutic efficacy in advanced or heterogeneous tumors, necessitating combined therapeutic strategies. Herein, we report a one-step emulsion fabrication strategy to develop agarose-encapsulated multifunctional microspheres (AEMMs) using low-cost, biocompatible agarose as the scaffold matrix. AEMMs co-encapsulate PSS for electrostatic drug binding, iodixanol as a dual-contrast agent for CT and DSA, and superparamagnetic Fe₃O₄ nanoparticles that serve as both MRI contrast agent and NIR photothermal converter. In vitro evaluation demonstrates that AEMMs achieve ultrahigh drug loading capacities of 89.87 ± 1.78 mg/mL for DOX or 90.60 ± 0.84 mg/mL for Irinotecan, which are comparable to commercial CalliSpheres^® and nearly twofold higher than DC Beads^®. Photothermal evaluation confirms that AEMMs induce rapid temperature elevation above 50 °C within 3 min under 808 nm laser irradiation, with excellent thermal stability and reproducibility over repeated on-off cycles. Furthermore, AEMMs provide excellent complementary contrast for CT, DSA, and T₂-weighted MRI, enabling real-time embolization monitoring and postoperative assessment. Blank AEMMs exhibit negligible cytotoxicity against HepG2 cells even at high concentrations, verifying favorable biocompatibility. Collectively, AEMMs integrate mechanical embolization, localized sustained chemotherapy, on-demand photothermal ablation, and multimodal imaging guidance into a single platform, offering a rational and promising integrated strategy to overcome the key limitations of conventional TACE for advanced HCC management.