Calcium ascorbate loaded ultrathin ferrous sulfide nanosheets thermo-sensitive hydrogels for near-infrared light activation of synergistic endometriosis therapy

Endometriosis can cause endometrial inflammation and affect women's reproductive health. However, it's still challenging to develop efficient endometriosis treatment strategies until now. Herein, a novel near-infrared light (NIR)-activated hydrogel nanostructure (Vc-Ca/UFNs@Gel) with ultrathin ferrous sulfide nanosheets (UFNs) and calcium ascorbate (Vc-Ca) was developed for in situ photothermal/ferroptosis/immune synergistic endometriosis therapy. UFNs with high photothermal conversion efficiency can convert NIR into heat to achieve efficient photothermal therapy (PTT) of endometrial cells, and simultaneously melt the hydrogels to achieve the release of Vc-Ca and UFNs. Vc-Ca can greatly prevent UFNs with ultrathin nanostructure from oxidation and keep their photothermal capacity, as well as directly inhibit the proliferation of endometrial cells. UFNs with dose-dependent internalization decomposed into H2S and Fe2+ ions in endometrial cell, catalyzing the self-oxidation process of Vc-Ca to generate H2O2 and enhancing Fe2+-triggered ferroptosis of endometriosis. Interestingly, ferroptosis and PTT-triggered endometrial cell apoptosis could also induce immunogenic cell death and enhance subsequent immunotherapy. Importantly, our hydrogels can be degradable in vivo with high safety. Overall, our work proposed a novel in situ photothermal/ferroptosis/immune synergistic endometriosis therapy strategy and may have significantly potential clinical application prospects.