Enhancing cancer therapy via acoustics: chemotherapy-enhanced tunable acoustofluidic permeabilization (ChemoTAP).

Mechano-chemo cancer treatment is an emerging therapeutic strategy that enhances chemotherapy efficacy by combining chemical agents with mechanical forces to improve drug uptake and overcome resistance. However, current approaches for delivering mechanical forces, including magnetic stress, hydrodynamic shear, and ultrasonic cavitation, suffer from limited tunability, poor spatial precision, and off-target effects, restricting their clinical potential. Here, we introduce ChemoTAP (chemotherapy-enhanced tunable acoustofluidic permeabilization), an acoustofluidic system that utilizes standing surface acoustic waves (SAWs) to achieve highly localized, tunable mechanical stimulation, enhancing tumor cell permeability and improving chemotherapeutic efficiency. By fine-tuning SAW parameters, ChemoTAP transiently modulates membrane permeability by activating mechanosensitive ion channels, leading to cytoskeletal remodeling and a 2.73-fold increase in intracellular calcium ion flux in HeLa cells. This SAW-induced mechanotransduction response synergistically enhances the cytotoxic effects of cisplatin, increasing tumor cell apoptosis by 1.78-fold through mitochondrial membrane depolarization, reactive oxygen species generation, and endoplasmic reticulum stress pathways. Unlike conventional ultrasound-based cavitation methods, ChemoTAP enables precise, non-invasive mechanical stimulation without requiring microbubbles, offering a controllable and scalable alternative for mechano-chemo cancer treatment. ChemoTAP establishes a foundation for further studies in mechanotherapy treatment pathways and promotes the broader integration of acoustics in oncology.