Abstract

Anxiety and mood disorders, notably major depressive disorder characterized by suppressed neuronal excitability, involve disruption of endogenous molecular polarity homeostasis. Conventional monoamine antidepressants, constrained by delayed therapeutic onset and high risk of drug resistance, neglect and fail to address this pathological feature. Here, we report IC@His-ICG, a near-infrared-responsive photochemical nanomotor that enables polarity switching. Leveraging photochemically driven polarity change, the wireless nanomotors achieved ion-tolerant propulsion in physiological media and phototactic migration to predefined hippocampal targets. Spatiotemporal polarity tuning induced instantaneous calcium oscillations and hippocampal excitation transmission, restoring monoamine homeostasis and combating anxiety and depression in rodents. This polarity-based neuromodulation operates independently of ligand-receptor mechanisms, linking nanoscale polarity dynamics to neurochemical homeostasis and behavioral outcomes in a depressive mouse model. The noninvasive, precision nanomachine strategy differs from traditional intervention frameworks, offering a precise modulation approach for neural disorders.