The purpose of current research is to develop ultrasound-triggered gas-generating Doxorubicin PLGA nanoparticle for cancer therapy. Method: pH-sensitive PLGA nanoparticles (PLGANPs) was fabricated to deliver doxorubicin (DOX) and sodium bicarbonate (NaHCO₃) using the water-in-oil-in-water (w/o/w) double emulsion method. Result: The nanoparticle with the size (650 nm) and high drug loading (15.8±2.3%) were successfully prepared and showed pH-responsive release characteristics. In vitro results indicate that DOX/NaHCO₃@PLGANPs with ultrasound had higher inhibition and cell uptake on MCF-7 cells than free DOX and other formulation. In vivo animal experiments showed that after treatment of DOX/NaHCO₃@PLGANPs with ultrasound, the relative tumor volume (0.63) of S180-tumor-bearing mice was lower than that of without ultrasound (0.81), DOX@PLGANPs (1.00) and Free DOX (1.12). Moreover, safety evaluation result indicated that DOX/NaHCO₃@PLGANPs was safer than free DOX. In conclusion, the DOX/NaHCO₃@PLGANPs was successfully developed and evaluated In vitro and In vivo. This drug delivery system will be a promising strategy for cancer therapy and diagnosis.