.On-demand drug release is one of the main challenges in nanocarrier design and a key step toward enhancing the efficacy of novel therapeutic formulations. Compared to conventional methods such as pH- or light-driven release, ultrasound-guided drug release offers a cost-effective strategy with improved tissue penetration making it particularly suitable for applications in hard-to-access tissues such as pancreas. In this study, hollow nanoparticles (hPDA) were developed and evaluated for ultrasound-enhanced drug delivery, focusing on pancreatic ductal adenocarcinoma (PDAC). The hPDA nanoparticles, prepared employing non-toxic reagents, measured approximately 120 nm and were successfully loaded with SN-38, a potent yet challenging-to-formulate chemotherapeutic agent. Ultrasound-triggered drug release experiments at 60 kHz and 1.1 MHz demonstrated significant enhancements in drug release, with an increase of 54% and 19% respectively, compared to controls. Cytotoxicity studies under ultrasound exposure revealed a 20% reduction in cell viability, underscoring the synergistic potential of hPDA and ultrasound technology. These findings establish hPDA nanocarriers as a promising platform for ultrasound-responsive, targeted drug delivery in cancer therapy, with high potential for improved spatiotemporal control and reduced systemic toxicity.