Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

Abstract Sonodynamic therapy (SDT) is noninvasive and possesses high body‐penetration depth, showing great potential for the treatment of deep‐seated solid tumors. The efficacy of SDT, however, is limited by widespread hypoxia in solid tumors. Given this, an ultrasound‐activated nanosystem is developed by integrating ferrate(VI) and protoporphyrin IX into biodegradable hollow mesoporous organosilica nanoplatforms, followed by assembling a phase‐change material of lauric acid. The ferrate(VI) effectively reacts with water as well as overexpressed hydrogen peroxide and glutathione (GSH) in tumor cells, leading to tumor‐microenvironment‐independent oxygen production and in situ GSH depletion in tumors. More importantly, significant reactive oxygen species (ROS) overproduction is simultaneously achieved by protoporphyrin‐augmented SDT and intracellular Fenton chemistry. Furthermore, the mild hyperthermia induced by ultrasound can trigger the phase change of lauric acid, achieving ultrasound‐responsive control over the release of oxygen and ROS, and the depletion of GSH. The simultaneous oxygen generation, in situ GSH depletion, and ROS overproduction play a synergetic role in sensitizing SDT toward hypoxic solid tumors, which is verified by the remarkable improvement of hypoxic environments and more significant growth inhibition of SDT against osteosarcoma both in vitro and in vivo, showing promising application in hypoxic solid tumor treatment.