iRGD-targeted nanoliposomes for hypoxia-relieved sonodynamic and ferroptosis-enhanced chemodynamic combination cancer therapy.

Current clinical interventions for solid tumors are confronted with multiple prominent challenges, including intratumoral hypoxia, constitutively activated endogenous antioxidant defense systems, and inefficient tumor targeting. In this study, a multifunctional nanoliposome carrier is developed by co-encapsulation of hemoglobin (Hb), ferric citrate (FC), and chlorin e6 (Ce6), and surface-modified with the iRGD (CRGDKGPDC) peptide to facilitate active tumor targeting and enhance subsequent intratumoral penetration. Under ultrasound irradiation, the iRGD-targeted nanoliposomes can efficiently generate two distinct types of reactive oxygen species (ROS) to produce strong synergistic cytotoxicity against 4T1 breast cancer cells via separate pathways: singlet oxygen (1O₂) through the sonodynamic therapy (SDT) pathway, and hydroxyl radicals (·OH) through the chemodynamic therapy (CDT) pathway. In vivo experimental results show that tail vein injection (i.v.) of iRGD-targeted nanoliposomes combined with external ultrasound irradiation achieves can significantly enhance tumor growth inhibition, which is attributed to triggered on-demand drug release induced by ultrasound. The as-prepared iRGD-targeted nanoliposomes exhibit remarkable synergistic antitumor efficacy, inducing extensive tumor necrosis, apoptosis, and ferroptosis while causing minimal systemic side effects, demonstrating great application potential for future breast cancer therapy.