Remotely disturbing bioelectrical homeostasis by nanoparticle-enabled intracellular electrical stimulation for wireless cancer therapy

Bioelectrical homeostasis plays critical roles in biological processes, but disturbing it for cancer therapy remains challenging due to the difficulty in electrically controlling cancer cells. Here we show that cell-internalized electroactive nanoparticles interrupt it in cancer cells to effectively treat cancer wirelessly. Specifically, K0.5Na0.5NbO3 ferroelectric nanoparticles are polarized and then generate a voltage of approximately −60 mV in response to ultrasound. Hence, once endocytosed by cancer cells in tumors, these nanoparticles establish an intracellular electric field (iEF) under the remote activation by ultrasound irradiation (for only 3 min) from outside the body. The iEF then depolarizes cell membrane potentials, decreases mitochondrial membrane potentials, and overloads intracellular calcium ions, disturbing intracellular bioelectrical balance. This disturbance promotes cancer cell apoptosis, inhibiting the growth of different types of tumors (bone tumor and skin tumor) without adverse effects. It is noteworthy that iEF can specifically disrupt the bioelectric balance of tumor cells but has no effect on normal cells. Such wireless cancer therapy can be achieved by other ferroelectric nanoparticles (e.g., BaTiO3). This work represents the first cancer treatment paradigm by intracellularly interrupting bioelectrical homeostasis remotely to cause cancer cell dysfunctions without electrode implantation and wire connection in vivo. It can also provide biologists with new tools for studying the role of disturbed bioelectrical homeostasis in cell fates and disease progression.