Ultrasound-Activated Paclitaxel Prodrug Potentiates Suppression of Tumor Growth and Metastasis

Paclitaxel (PTX) remains a first-line chemotherapeutic agent, yet its therapeutic index is limited by poor tumor selectivity, nonspecific biodistribution, and systemic toxicity. Here, we report an ultrasound (US)-activated PTX prodrug nanoplatform (PTX@TBR NPs) for tumor-selective and spatiotemporally controlled PTX activation. PTX was covalently masked with a US-responsive thioketal (TK) linker and conjugated to a polymer, while riboflavin tetrabutyrate (TBR), a vitamin B₂-derived sonosensitizer, was coencapsulated to enable sonochemical activation. Upon US irradiation, TBR generated singlet oxygen (¹O₂), which oxidized the TK linker and triggered its cleavage, thereby enabling on-demand PTX release with an efficiency of up to 68.0%. In vivo, PTX@TBR NPs+US achieved potent tumor inhibition, with a tumor suppression rate of 80.1%. Unexpectedly, this treatment also markedly suppressed distant metastasis. Transcriptomic analysis revealed broad downregulation of genes associated with redox-related metabolism, extracellular matrix remodeling, and lipid metabolic pathways, suggesting that sonochemical activation and PTX release cooperatively disrupted redox homeostasis, cytoskeletal functions, and metabolic adaptation. This study establishes a sonochemically amplified prodrug activation strategy for selective PTX chemotherapy and the inhibition of tumor growth and metastasis.