Gasotransmitter‐Nanodonor for Spatial Regulation of Anxiety‐Like Behavior and Bone Metastasis

Abstract Anxiety is highly prevalent among cancer patients, significantly impacting their prognosis. Current cancer therapies typically lack anxiolytic properties and may even exacerbate anxiety. Here, a gasotransmitter‐nanodonors (GND) system is presented that exerts dual anxiolytic and anti‐tumor effects via a “tumor‐brain axis” strategy. The GND, synthesized by co‐embedding Fe 2 ⁺ and S 2 ⁻ ions along with glucose oxidase (GOx) within bovine serum albumin (BSA) nanoparticles (FSG@AB), enables the controlled release of the gasotransmitter hydrogen sulfide (H₂S) in the acidic tumor microenvironment. H₂S and GOx synergistically deplete tumor energy sources, resulting in robust anti‐tumor effects. Meanwhile, H₂S generated at the tumor site is transported through the bloodstream to the anterior cingulate cortex (ACC) in the brain, where it modulates neuronal activity. Specifically, in the ACC, H₂S upregulates glutamate transporter 1 (GLT‐1), which reduces extracellular glutamate levels and attenuates the hyperactivity of glutamatergic neurons, thereby alleviating anxiety‐like behavior. This study proposes a GND system that targets both oncological and psychiatric dimensions of cancer through the “tumor‐brain axis” strategy, resulting in improved therapeutic outcomes.