Nitric Oxide-Mediated Minimally Invasive Neuromodulation through Gut-Brain Axis via a Bioelectronic Microdevice for Relieving Depressive Symptoms

Minimally invasive brain modulation is essential for understanding and treating neurological disorders. This study presents a wireless, optically controlled nitric oxide (NO)-releasing microbioelectronic device (ONMD) that enables peripheral-to-central neuromodulation without direct brain intervention. Upon light activation, the ONMD releases NO to locally activate transient receptor potential (TRP) channels, forming a confined NO-TRP signaling hub that selectively stimulates the vagus nerve and activates the nucleus tractus solitarius (NTS), a key brainstem center involved in autonomic and reward regulation. Through this hierarchical pathway, the ONMD-mediated neuromodulation alleviates depressive-like behaviors in mice, accompanied by reduced peripheral inflammation and restored central serotonin (5-HT) homeostasis. Operating in the intestine, the ONMD achieves remote modulation of central circuits through peripheral access. This gasotransmitter-mediated, multilevel bioelectronic approach offers a noninvasive strategy for regulating brain function and advancing neuropsychiatric therapies.