Inspired by considerable application potential in various diseases, nitric oxide (NO) has gained increasing attention. Nevertheless, current NO release scaffolds suffer from some inevitable drawbacks, for example, high toxicity for NO donor byproducts, poor specificity, shallow penetration depth, and strong ionizing irradiation for triggers, all of which remain obstacles to clinical application. Herein, an ultrasound-triggered NO on-demand release system is constructed using natural L-arginine as NO donor and local ultrasound as trigger. The focused ultrasound can activate H2O2 to generate more oxygen-contained species (ROS) of stronger oxidation ability than H2O2 for oxidizing LA via the energy transformation from ultrasound mechanical energy to chemical energy, and thus produce more NO for ultimately suppressing the highly aggressive and lethal Panc-1 tumor. Moreover, a blood vessel intercellular matrix cell "relay" targeting strategy has been established and relying on it, over 7-fold higher retention of such NO release system in a subcutaneous xenograft mouse model of Panc-1 is obtained, which consequently results in a more evident inhibitory effect and a prolonged survival rate (80% +/- 5% improvement in 60-day survival).