Tumor Metabolism-Engineered Composite Nanoplatforms Potentiate Sonodynamic Therapy via Reshaping Tumor Microenvironment and Facilitating Electron-Hole Pairs' Separation

Reactive oxygen species (ROS) depletion and low ROS production that result from the intratumoral redox metabolism equilibrium and low energy conversion efficiency from ultrasound mechanical energy to ROS-represented chemical energy, respectively, are two vital inhibitory factors of sonodynamic therapy (SDT). To address the two concerns, a tumor metabolism-engineered composite nanoplatform capable of intervening intratumoral ROS metabolism, breaking the redox equilibrium, and reshaping the tumor microenvironment is constructed to reinforce SDT against tumors. In this metabolism-engineered nanoplatform, Nb2C nanosheets serve as the scaffold to accommodate TiO2 sonosensitizers and l-buthionine-sulfoximine. Systematic experiments show that such nanoplatforms can reduce ROS depletion via suppressing glutathione synthesis and simultaneously improving ROS production via the Nb2C-enhanced production and separation of electron-hole pairs. Contributed by the combined effect, net ROS content can be significantly elevated, which results in the highly efficient anti-tumor outcomes in vivo and in vitro. Moreover, the combined design principles, that is, tumor metabolism modulation for reducing ROS depletion and electron-hole pair separation for facilitating ROS production, can be extended to other ROS-dependent therapeutic systems.