¹⁷⁷ Lu‐Loaded Composite Microspheres with Micro/Nano‐Structure for Radioembolization Therapy of Hepatocellular Carcinoma

ABSTRACT Transarterial radioembolization (TARE) is a well‐established therapy for hepatocellular carcinoma. However, existing radioembolic microspheres face limitations, such as single size selection, poor elasticity, lack of theranostic integration, and insufficient stability, which limit their clinical application in TARE. In this study, polydopamine@chitosan (PDA@CS) microspheres featuring a micro‐nano composite structure are fabricated by a facile microfluidic method. These microspheres stably chelate Lu 3+ (forming 177 Lu‐PDA@CS microspheres) through catechol‐metal coordination via the phenolic hydroxyl groups of PDA nanoparticles (PDA NPs). The compact structure of the microspheres with uniformly incorporated PDA NPs ensures radioactive stability through dual retention mechanisms: chemical retention via phenolic hydroxyl groups and physical retention by microsphere matrix. These microspheres exhibit uniform and precisely tunable sizes, good biocompatibility, appropriate elasticity, structural stability, and integrated theranostic capabilities. Key properties of PDA@CS microspheres, including morphology, elasticity, loading capacity and binding stability of Lu 3+ , can be regulated by adjusting the PDA NPs concentration in the internal fluid phase. In vivo TARE studies in rat models demonstrate that 177 Lu‐PDA@CS microspheres not only retain well within the hepatic artery, but also effectively inhibit tumor growth and metastasis while maintaining excellent biosafety. The proposed radioembolic microspheres show significant potential as an innovative radioembolic agent for primary liver cancer.