Second near-infrared photoactivatable hydrogen selenide nanogenerators for metastasis-inhibited cancer therapy

• Ferrous selenide nanoflowers realize photothermal effect and H 2 Se gas generation under second near-infrared laser irradiation. • The sustained accumulation of H 2 Se in tumor cells down-regulates the expression of HMGB1 protein to cause cell autophagy. • Ferrous selenide nanoflower-mediated synergistic photothermal-autophagy therapy effectively suppresses the growth of subcutaneous breast tumors and completely inhibit liver and lung metastasis. Hydrogen selenide (H 2 Se) plays key roles in diverse physiological processes; however, the noninvasive regulation of H 2 Se levels in living systems has been rarely achieved and the functional mechanism of H 2 Se in cancer cells remains unclear. Herein, biocompatible ferrous selenide (FeSe 2 ) nanoflowers with second near-infrared (NIR-Ⅱ) photoactivatable H 2 Se generation were developed for metastasis-inhibited cancer therapy. Upon NIR-II laser irradiation, FeSe 2 nanoflowers generated mild photothermal effect, leading to their decomposition and on-demand release of H 2 Se to induce cell death. Such a FeSe 2 nanoflower-mediated synergistic photothermal-H 2 Se gas therapy effectively suppressed the tumor growth in a subcutaneous breast tumor-bearing mouse model. Furthermore, the local generation of H 2 Se was proved to down-regulate the expression levels of metastasis-related proteins, contributing to the complete inhibition of liver and lung metastasis. Overall, we report a NIR-Ⅱ photoactivatable H 2 Se production strategy for metastasis-inhibiting cancer therapy, which may be mediated by autophagy, opening a new avenue for the biomedical application of H 2 Se in the future.