Acoustic vaporization of internalized nanodroplets enables macrophage ablation and intracellular drug release

Phase-change nanodroplets (PCND) represent an emerging ultrasound-responsive platform that undergoes acoustic droplet vaporization (ADV), generating localized biomechanical effects. In this study, we leverage this acoustic mechanism to ablate macrophages and enhance intracellular drug release in a tumor-relevant context. Macrophages are known to serve as reservoir for nanodrugs, such as liposomal doxorubicin. In this study we generate PCND that are taken up by macrophages and we explode whether metronomic drug release from these cells can be enabled by ultrasound based PCND vaporization. Lipid-shelled PCND (mean diameter ∼195 nm) were synthesized using perfluoropentane and internalized efficiently by J774a.1 macrophages after 4 h of co-incubation. Upon exposure to 16-MHz ultrasound at a peak negative pressure of 4.19 MPa, vaporization of intracellular PCND-induced significant disruption of cellular membranes, resulting in macrophage ablation. Furthermore, when macrophages were preloaded with liposomal doxorubicin (Doxil®), ultrasound activation triggered substantial intracellular drug release, leading to elevated extracellular drug concentrations. This acoustically mediated mechanism enables spatially targeted immune cell depletion and drug liberation, providing a dual-function strategy for modulating the tumor microenvironment. Our findings highlight the potential of ADV-capable PCND as a controllable acoustic actuator for localized immunomodulation and enhanced chemotherapeutic delivery.