Neural Engineering Tailored by Molecular Motors With Self‐Reporting for Neuron Activation and Depression Treatment

The discovery of mechanical regulation to neuronal behavior offers a novel perspective for understanding nervous system function and advancing neural engineering. A key challenge lies in achieving precise mechanical control of neurons while simultaneously monitoring their activity in real time. Here, we engineered a novel molecular machine equipped with self‐reporting capability, MM‐VSD1, enabling stable anchoring into the plasma membrane. This integrated molecular tool comprises a light‐driven rotary molecular motor (MM), which delivers localized mechanical force to neuronal membranes. Concurrently, a tethered near‐infrared voltage‐sensitive dye (VSD1) module provides real‐time fluorescent feedback on changes in membrane potentials with millisecond temporal and subcellular spatial resolution. Utilizing this bifunctional molecular device, we demonstrate that MM‐VSD1 effectively activates mechanosensitive TRPV1 ion channels in hippocampal neurons, triggering calcium influx and action potential (AP) firing. This mechanical modulation induced by MM‐VSD1 is persistent and can be evoked in vivo up to one week, providing the potential of MM‐VSD1 for alleviating depression‐like behaviors in mice. By bridging mechanical manipulation with functional readouts at high spatiotemporal resolution, our work opens an avenue for mechano‐based therapeutic interventions in neurological disorders.