An Ultrasound‐Responsive Pickering‐Like Emulsion for Dual‐Amplified Sonodynamic/Cuproptosis Synergistic Therapy via Tumor Microenvironment Remodeling

ABSTRACT Sonodynamic therapy (SDT) combined with cuproptosis is promising but remains limited by glutathione (GSH)‐dominated antioxidant defense and severe hypoxia in the tumor microenvironment (TME). Conventional emulsions rarely dismantle both barriers while maintaining sufficient stability for tumor accumulation. Herein, we report Pickering‐like emulsions (PFTC EMs) that overcome these challenges through ultrasound‐triggered cascade responses. PFTC EMs comprise oxygen‐loaded perfluorohexane droplets armored with copper‐coordinated TCPP nanoparticles (FTC NPs). Benefiting from improved colloidal stability and prolonged circulation, PFTC EMs achieve two‐fold higher tumor accumulation than surfactant‐stabilized emulsions. Under ultrasound, PFTC EMs undergo structural disruption to co‐release FTC NPs and oxygen for dual‐pronged TME remodeling, enabling FTC NPs‐mediated GSH depletion and oxygen‐mediated hypoxia alleviation. TME remodeling potentiates SDT efficacy. Synergistically, ultrasound‐triggered Cu + generation induces oligomerization of lipoylated proteins to initiate cuproptosis, while hypoxia alleviation amplifies cuproptosis by restoring cellular respiration. The resulting oxidative‐proteotoxic stress triggers immunogenic cell death and promotes dendritic‐cell maturation. Collectively, PFTC EMs suppress tumors and elicit antitumor immunity in vivo. This work establishes an intelligent “cluster bomb”‐based TME‐remodeling paradigm to amplify multimodal antitumor therapy.