Targeting Vascular Destruction by Sonosensitizer-Free Sonocatalytic Nanomissiles Instigates Thrombus Aggregation and Nutrition Deprivation to Starve Pancreatic Cancer

Sonosensitizers in current sonodynamic therapy (SDT) often suffer from poor delivery efficiency, phototoxicity, and disputed safety. To overcome these issues, a sonosensitizers-free sonocatalytic nanomissile is constructed, wherein PLGA nanoparticles as vehicles conjugate with L-arginine (LA) and aptamer XQ2d capable of adsorbing CO2 and targeting CD71-overexpressed pancreatic cancer, respectively. The adsorbed CO2 can respond to acidic tumor microenvironment and local ultrasound to release CO2 bubbles and enhance ultrasound-triggered inertial cavitation, which can further split H2O and activate dissolved O2 to produce center dot OH and 1O2, respectively, unlocking the sonosensitizers-free sonocatalytic ROS birth. Moreover, such CO2 bubbles-enhanced inertial cavitation also can target intratumoral vascular destruction, instigate thrombus aggregation, induce nutrition and oxygen deprivation, pose hypoxia and alter tumor metabolism, thus establishing an intratumoral vascular destruction-targeted starvation therapy. The strategy is different from previous starvation therapy in which the presence of undamaged intratumoral blood vessels compromises their outcomes. Especially, the active targeting aptamer XQ2d allows more sonosensitizer-free sonocatalytic nanomissiles to retain in pancreatic cancer, significantly magnifying the sonosensitizers-free sonocatalytic therapy and starvation therapy against subcutaneous and orthotopic pancreatic cancers. Therefore, the research provides a promising route and therapeutic platform for clinical pancreatic cancer therapy. Exogenous local ultrasound and endogenous low pH in tumor microenvironment together serve as the triggers to unlock sonosensitizers-free sonocatalytic ROS birth via activating CO2 release and enhancing inertial cavitation for directly killing pancreatic cancer cells. Beyond that, CO2 bubbles-enhanced cavitation gives birth to mechanical effects to destroy blood vessel and instigate thrombosis aggregation and nutrition deprivation, further repressing pancreatic cancer. image