• delivery
• microdroplets
• multi-drug
• ultrasound

This work explores the controlled release of multiple drugs through ultrasound(US)-responsive perfluorocarbon (PFC) droplets, using acoustic droplet vaporization. Two types of PFC droplets were studied, both with a perfluoropentane core containing fluorescein sodium salt, but with different shell compositions: lipid-based and surfactant-based. Microfluidics was used for synthesis, and low-intensity pulsed US (38 kHz, 20%, 100 Hz, 5 min) was applied at 25–125 kPa. Morphological changes were analyzed by Hirox microscopy; drug release was quantified with the Victor Nivo system. At 50 kPa, lipid-shelled droplets ruptured and released 28% of their content, while surfactant-shelled droplets remained intact. Efficient release from surfactant droplets (33%) required 100 kPa. These results show that different activation thresholds enable sequential, pressure-controlled release of two drugs. This approach may support the future development of US-responsive patches or scaffolds for multi-drug delivery.