H 2 S‐Releasing Aspirin Nanoparticles Alleviate Endometriosis and Associated Anxiety

ABSTRACT 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 (H 2 S)‐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 H 2 S 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, H 2 S 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.