Spatiotemporally Ultrasound-Activatable Self-Amplifying Biomimetic Liposomes for Imaging-Guided Synergistic Cancer Sonodynamic Chemotherapy

Overcoming hypoxia and enhancing therapeutic precision remain critical challenges for sonodynamic therapy (SDT) in oncology. Herein, we develop a biomimetic liposomal platform (DiR-VT@cmLipo) coencapsulating the sonosensitizer verteporfin (VP) and hypoxia-activated prodrug evofosfamide (TH302), which synergistically inhibits tumor progression via fluorescence imaging-guided ultrasound-activated spatiotemporally selective sonodynamic-chemotherapy. Engineered with natural membrane components, DiR-VT@cmLipo exhibits prolonged systemic circulation while maintaining precise tumor-specific accumulation after intravenous injection. The therapeutic cascade was precisely initiated through an ultrasound-triggered VP-mediated ROS burst, simultaneously consuming intratumoral oxygen. This creates a self-amplifying hypoxia gradient to promote the activation of cytotoxic payload TH302, enhancing SDT efficacy through synergistic mechanisms. This biomimetic nanoplatform represents an innovative strategy for overcoming microenvironmental limitations in SDT, establishing a paradigm for synergistic tumor microenvironment remodeling and precision-controlled combination therapy. The cascaded self-amplifying activation mechanism and spatiotemporally tumor-selective therapeutic amplification position DiR-VT@cmLipo as a promising candidate for clinical translation in solid tumor management.