A neural network-inspired electric field mediated by piezoelectric nanoparticles repolarizes macrophages to potentiate anticancer immunotherapy

Repolarizing tumor-associated macrophages (TAMs) toward the proinflammatory M1 phenotype represents a promising strategy to reverse the immunosuppressive tumor microenvironment (TME) and enhance antitumor immunotherapy. Recent studies have demonstrated that exogenous electrical stimulation can effectively repolarize TAMs toward the M1 phenotype. However, conventional electrical stimulation methods, relying on invasive implanted electrodes, are restricted to targeting localized tumor regions and pose inherent risks to patients. Notably, biological neural networks, distributed systems of interconnected neurons, can naturally permeate tissues and orchestrate cellular activities with high spatial efficiency. Inspired by this natural system, we developed a global in situ electric field network using piezoelectric BaTiO₃ nanoparticles. Upon ultrasound stimulation, the nanoparticles generate a wireless electric field throughout the TME. In addtion, their nanoscale size enables them to function as synthetic “neurons”, allowing for uniform penetration throughout the tumor tissue and inducing significant repolarization of TAMs via the Ca²⁺ influx-activated nuclear factor-kappa B (NF-κB) signaling pathway. The repolarized M1 TAMs restore anti-tumor immunostimulatory functions and secrete key proinflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)), which enhance immunostimulation within the TME and directly contribute to tumor cell elimination. Remarkably, this strategy achieved robust in vivo tumor growth inhibition with excellent biosafety in a 4T1 breast tumor model. Overall, this work establishes a non-invasive, wireless electric field platform capable of globally repolarizing TAMs, offering a safe and efficient strategy to advance cancer immunotherapy and accelerate the clinical translation of bioelectronic therapies.