  Background: The development of smart nanocarriers that enable controlled drug
release in response to internal and external triggers is an emerging approach
for targeted therapy. This study focused on designing pH-sensitive,
ultrasound-responsive gelatin/perfluorohexane (PFH) nanodroplets loaded with
berberine chloride as a model drug. Results:The nanodroplets were prepared
using an emulsion technique and optimized by varying process parameters like
homogenization rate, polymer concentration, surfactant, drug, and
perfluorocarbon content. The optimal formulation yielded nanodroplets with a
particle size of 281.7 nm, a drug encapsulation efficiency of 66.8+- 1.7%, and
a passive drug release of 15.4+- 0.2% within 24 hours. Characterization
confirmed successful encapsulation and pH-responsive behavior. Ultrasound
stimulation significantly enhanced drug release, with 150 kHz being more
effective than 1 MHz in triggering acoustic droplet vaporization while
minimizing heat generation. After 10 minutes of radiation, the optimal
formulation showed 89.4% cumulative drug release. The nanodroplets displayed
stability over one month at 4{\deg}C. Conclusions: Overall, the dual-triggered
nanodroplets demonstrate excellent potential for controlled delivery and
targeted release of berberine chloride.
