Mitochondrial Targeting Amplifies Photothermal–Chemotherapy Synergy to Combat Paclitaxel-Resistant Breast Cancer

Mitochondria have emerged as critical therapeutic targets in anticancer strategies, particularly for overcoming the inherent resistance challenges during tumor treatment. Herein, we present a metallodrug delivery system (FT-lipoAu/PTX) with multistage targeting capability, designed to achieve mitochondria-specific photothermal apoptosis and reverse tumor chemoresistance. FT-lipoAu/PTX was composed of folic acid (FA) and triphenylphosphonium (TPP)-modified paclitaxel (PTX) liposomes encapsulating gold nanorods (AuNRs). FA and TPP dual modification enable multistage targeting of folate receptor-overexpressing breast tumor cells, facilitating FT-lipoAu/PTX accumulation in mitochondria. Under near-infrared (NIR) laser irradiation, FT-lipoAu/PTX generated localized hyperthermia, triggering mitochondrial membrane potential depolarization, cytochrome c release, reduced cellular metabolic efficiency, and suppressed ATP synthesis. Importantly, this tumor metabolic reprogramming process significantly downregulated drug-resistance protein expression [e.g., efflux pump P-glycoprotein (P-gp)], thereby increasing intracellular PTX retention and enhancing chemotherapeutic efficacy. In a chemoresistant breast tumor murine model, FT-lipoAu/PTX demonstrated prolonged circulation, high tumor specificity, potent tumor growth suppression, and minimal systemic toxicity. Collectively, FT-lipoAu/PTX leveraged mitochondria-targeted phototherapy to overcome chemoresistance barriers, providing a robust strategy for effective chemotherapy.