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 Fe2+ 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.