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 Fe²⁺ and S²⁻ 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.