Ferroptosis-triggered monodisperse microspheres for transcatheter arterial embolization of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) presents a major clinical challenge because of its high death rate and few treatment options. This study introduces an innovative therapeutic platform that combines transarterial embolization (TAE) with ferroptosis induction for enhanced HCC treatment. We developed monodisperse erastin-loaded microspheres using a microfluidic technique, with a biodegradable PLA-PEG-PLA copolymer as the matrix material. By adjusting the flow rate and concentration of the continuous and disperse phases, the particle size and distribution were precisely controlled. Importantly, drug release kinetics and antitumor efficacy were effectively regulated by modulating the hydrophobic segment molecular weight of the copolymer, with lower molecular weights PLA chains facilitating faster release and superior therapeutic outcomes. In vitro and in vivo evaluations demonstrated that erastin-loaded microspheres significantly inhibited tumor growth through ferroptosis induction, outperforming bare microspheres in a VX2 rabbit model. The increased efficacy is due to the combined effects of vascular embolization and ferroptosis. This work establishes a novel treatment paradigm that integrates material design with molecular mechanism for effective interventional therapy, offering a promising translational strategy for HCC management.