Dual‐Targeting Nanomicelles Co‐Loading Sorafenib and Artesunate Combats Hepatocellular Carcinoma via the Synergistically Enhanced Ferroptosis Strategy

ABSTRACT

Hepatocellular carcinoma (HCC) remains a formidable malignancy with limited response to conventional monotherapies, largely due to its complicated pathogenesis and useful cellular defense systems. In this study, we constructed a dual‐targeting polymeric micelle (S&A@TPD/HG PMs), co‐delivering sorafenib (SOR), and artesunate (ART) to achieve synergistic ferroptosis‐based therapy against HCC. The micelle features a hyaluronic acid (HA) shell functionalized with glycyrrhetinic acid (GA) for active dual targeting to CD44 and GA receptors overexpressed on HCC cells; while its triphenylphosphonium (TPP)‐decorated inner core facilitates mitochondrial anchoring and co‐conveys the drugs, enabling stepwise subcellular targeting. Compared with free drugs or single‐drug‐loaded micelles, S&A@TPD/HG PMs effectively induced mitochondrial damage by depleting glutathione (GSH), and downregulating GSH peroxidase 4 (GPX4) expression to disrupt the mitochondrial antioxidant defense system, elevating intracellular Fe ²⁺ to increase reactive oxygen species (ROS) and lipid peroxidation (LPO) production, thereby compromising mitochondrial redox homeostasis and potentiating ferroptosis jointly. This ferroptosis‐inducing activity yielded potent in vivo antitumor efficacy in Huh‐7 tumor‐bearing nude mice, with a tumor inhibition rate of 74.23% and minimal systemic toxicity. Collectively, the organelle‐specific targeting combined with co‐delivery of synergistic drug pairs represents a promising strategy for combating malignancies and provides a blueprint for the rational design of multifunctional nanosystems.