H₂S-Releasing Aspirin Nanoparticles Alleviate Endometriosis and Associated Anxiety

Despite ongoing challenges in developing effective non-surgical and non-hormonal treatments for endometriosis, the psychological manifestations of the disease-particularly anxiety-remain comparatively underexplored. In this study, a hydrogen sulfide (H₂S)-releasing aspirin derivative, ACS14, was encapsulated in albumin nanoparticles (ACS14@BSA) for targeted delivery. Upon intraperitoneal injection in a mouse model of endometriosis, ACS14@BSA was selectively transported to ectopic lesions via a neutrophil hitchhiking strategy. There, it inhibited ectopic cell proliferation by modulating the PI3K/Akt pathway and reduced inflammation by suppressing the NF-κB pathway, exerting a comprehensive therapeutic effect on endometriosis. Simultaneously, the H₂S released at lesion sites was conveyed through the bloodstream to the anterior cingulate cortex (ACC), a brain region critical for anxiety regulation, as demonstrated by in vivo fiber photometry recordings in mice. Importantly, in the ACC, H₂S upregulated glutamate transporter 1 (GLT-1), decreased extracellular glutamate levels, and dampened glutamatergic neuron hyperactivity, thereby alleviating endometriosis-associated anxiety. This study presents a novel gasotransmitter-releasing nanoplatform that offers a non-invasive and non-hormonal approach for the concurrent treatment of endometriosis and associated anxiety.