Ultrasound‐Activated Sonophage Synergizes Sonodynamic Therapy and Saltoptosis for Solid Tumor Eradication

Abstract Sodium overload has emerged as a novel antitumor approach, which is termed as “saltoptosis,” due to its significant therapeutic potential. However, its inherent limitations and related solid tumor treatment challenges have impeded clinical translation. A synergistic strategy integrating saltoptosis with sonodynamic therapy (SDT) is proposed to enhance therapeutic efficacy. Specifically, a M1 macrophage extracellular vesicle‐liposome hybrid (termed “Sonophage”), encapsulating sonosensitizer (Ce6), oxygen‐enriched perfluorocarbon (PFC‐O 2 ), and salt solution (brine), is engineered. This innovative design enables the simultaneous activation of sonodynamic saltoptosis. Under ultrasound, Sonophage directly damages tumor cells via SDT while inducing immunogenic cell death. Concurrently, sodium overload, paired with the biological functions of M1 macrophage extracellular vesicles, reprograms the immunosuppressive tumor microenvironment by polarizing macrophages to a pro‐inflammatory M1 phenotype and enhancing T‐cell activation, key drivers of antitumor immunity. Additionally, PFC‐O 2 alleviates tumor hypoxia, amplifying the combined therapeutic impact. Preclinical studies show that Sonophage selectively targets and penetrates tumors, significantly inhibiting progression, priming systemic immunity to prevent metastasis, and ultimately extending survival. Transcriptomic analysis further confirms its potential to enhance immune responses against tumors. Thus, this combination therapy, where sondynamic waves in a sea of salt orchestrate a synergistic attack on tumors, offers a promising new avenue for advancing cancer treatment.