Acoustically Activatable Drug-Loaded Nanodroplets for Mechanochemical Therapy in Solid Tumors.

Stimulus-responsive nanomedicines promise controlled therapy, yet most systems rely on passive delivery and lack precise, externally programmable activation while maintaining clinical compatibility. Here we engineer sub-200 nm, perfluorocarbon (PFC)-core nanodroplets (ND) that integrate efficient drug loading, physiological stability, and acoustically programmable activation within a nanoscale agent. These NDs are fabricated using microfluidic nanoassembly to achieve controlled size and composition, and are designed to encapsulate fluorinated payloads within the liquid core. Upon exposure to sequential dual-frequency ultrasound (US), the NDs undergo acoustic droplet vaporization followed by low-frequency cavitation, enabling spatially confined disruption and on-demand payload release within clinically relevant acoustic limits. These properties are engineered to overcome physicochemical barriers in solid tumors, including dense extracellular matrix and restricted drug penetration. This approach achieves enhanced payload release and induces mechanochemical cytotoxicity in vitro. In vivo, NDs exhibit prolonged circulation and tumor accumulation, while US activation drives tissue fractionation, controls drug release, and increases subsequent nanoparticle uptake. When applied to a solid tumor model, this combined mechanochemical strategy improves tumor control and extends survival compared to either modality alone. These acoustically activatable NDs provide a versatile system for stimulus-responsive, site-targeted drug delivery and tumor disruption, with strong potential for clinical translation.