Engineering Nanoparticle Interfaces to Control Cavitation and Sonodynamic Activity

Abstract Nanoparticle-mediated sonodynamic therapy (SDT) represents a promising non-invasive strategy for cancer treatment that relies on ultrasound-triggered reactive oxygen species (ROS) generation. Its efficacy is governed by acoustic cavitation, a phenomenon capable of converting mechanical energy into highly localized chemical reactivity. Yet, the mechanisms by which nanoparticle surface engineering influences cavitation, ROS production, therapeutic performance, and biological selectivity remain poorly understood. Although nanoparticles can dramatically lower cavitation thresholds and amplify ROS production, maximizing these effects often comes at the expense of biocompatibility and safety. Here, we design and characterize a biomimetic lipid-coated ZnO-based nanosystem that balances ultrasound responsiveness with biological safety and effectiveness. Structural characterization by dynamic light scattering and small-/wide-angle X-ray scattering demonstrates that iron-doped ZnO nanocrystals were encapsulated within the lipid bilayer, forming a stable nanosystem with a compact lipidic shell. Combining ultrasound experiments with molecular dynamics simulations at large negative pressures, we investigate how surface passivation modulates cavitation. We show that cavitation in water preferentially nucleates at the bare nanoparticle−water interface. The passivation of the nanoparticle surface with a soft lipid bilayer, although essential to ensure colloidal stability, biocompatibility, and efficient cellular internalization, partially attenuates interfacial bubble formation and ROS generation. Despite partially attenuating cavitation, lipid-coated nanoparticles still retain sonodynamic activity and preferential ROS-associated cytotoxicity in multiple myeloma cell lines, while limited effects are observed in healthy cells. These findings identify the nanoparticle interface as a key regulator of cavitation and establish a rational design strategy for engineering nanoparticle-based sonosensitizers that balance therapeutic efficacy with biological safety, providing a versatile, safe, and effective platform for next-generation sonodynamic cancer therapy.