Ultrasound induced phase-transition and invisible nanobomb for imaging-guided tumor sonodynamic therapy

Sonodynamic therapy (SDT) kills tumor cells by converting molecular oxygen (O₂) into reactive oxygen species (ROS) using sonosensitizers and appropriate ultrasound (US) stimulation. However, pre-existing tumorous hypoxia severely limits SDT efficacy. Worse is that O₂ consumption during SDT will aggravate local hypoxia. In this study, we developed an O₂ self-supplied and lossless US-responsive detonation strategy to overcome the above limitation. This explores a perfluorohexane (PFH) bubbling-based "stealth camouflage" and a US-controlled on-demand system (RBC-HPBs/HMME/PFH) to realize US imaging-guided precise drug delivery and locally positioning tumor therapy. Compared with HPBs/HMME/PFH, the results showed that RBC encapsulation can promote cell phagocytosis. After US stimulation, the PFH phase change induced RBC instantaneous blasting. Simultaneous release of HMME and O₂ resulted in plenty of ROS production and the intracellular redox system imbalance, significantly enhancing their cytotoxicity. Following US imaging guidance, the greatly improved local ROS level and the anti-tumor effect were proved in 4T1 tumor-bearing mice for HMME and the O₂ synchronous co-transport system. Immunohistochemistry results proved that RBC-HPBs/HMME/PFH + US could significantly relieve tumorous hypoxia and reduce the microvessel density as an O₂ reservoir, which would block nutritional sources to starve tumor cells and inhibit their metastasis, achieving a cancer multi-mechanism treatment.