Ultrasound-Responsive Lipid Nanoplatform with Nitric Oxide and Carbon Monoxide Release for Cancer Sono-Gaso-Therapy

Local gas therapy is emerging as a potential cancer treatment approach due to its specificity as gas-containing molecules can be packed into a nanodelivery system to release the corresponding gaseous molecules around the tumor site upon a suitable stimulus. Single-gas therapy has been reported, while synergistic dual-gas therapy has rarely been reported. Herein, we report a dual-gas-containing nanoplatform for synergistic cancer gasotherapy upon ultrasound irradiation. First, a robust ultrasound-responsive lipid-coated nanosystem was prepared with suitable particle size and characteristics. A low-intensity ultrasound (1.25 W/cm²) was found to simultaneously modulate carbon monoxide (CO) and nitric oxide (NO) release from the nanosystem in media and CT26 colon cancer cells for efficient therapeutic effect. The intracellular release promoted the overgeneration of reactive oxygen species (ROS) and triggered cancer cell apoptosis synergistically. The in vivo test demonstrated that the optimal dual-gas-containing formulation efficiently inhibited tumor growth (by ∼87%) at relatively low doses upon ultrasound irradiation (1.25 W/cm², 5 min). This therapeutic efficacy shows that the current responsive lipid-coated delivery system has potential for ultrasound-triggered dual-gas therapy of both superficially and deeply seated cancers.