Ultrasound-Responsive\nLipid Nanoplatform with Nitric\nOxide and Carbon Monoxide Release for Cancer Sono-Gaso-Therapy

Local gas therapy is emerging as\na potential cancer treatment\napproach\ndue to its specificity as gas-containing molecules can be packed into\na nanodelivery system to release the corresponding gaseous molecules\naround the tumor site upon a suitable stimulus. Single-gas therapy\nhas been reported, while synergistic dual-gas therapy has rarely been\nreported. Herein, we report a dual-gas-containing nanoplatform for\nsynergistic cancer gasotherapy upon ultrasound irradiation. First,\na robust ultrasound-responsive lipid-coated nanosystem was prepared\nwith suitable particle size and characteristics. A low-intensity ultrasound\n(1.25 W/cm<sup>2</sup>) was found to simultaneously modulate carbon\nmonoxide (CO) and nitric oxide (NO) release from the nanosystem in\nmedia and CT26 colon cancer cells for efficient therapeutic effect.\nThe intracellular release promoted the overgeneration of reactive\noxygen species (ROS) and triggered cancer cell apoptosis synergistically.\nThe in vivo test demonstrated that the optimal dual-gas-containing\nformulation efficiently inhibited tumor growth (by ∼87%) at\nrelatively low doses upon ultrasound irradiation (1.25 W/cm<sup>2</sup>, 5 min). This therapeutic efficacy shows that the current responsive\nlipid-coated delivery system has potential for ultrasound-triggered\ndual-gas therapy of both superficially and deeply seated cancers.