Recently, nanozymes with
peroxidase (POD)-like activity have shown great promise for ferroptosis-based
tumor therapy, which are capable of transforming
hydrogen peroxide (H2O2) to highly toxic
hydroxyl radicals (•OH). However, the unsatisfactory therapeutic performance of nanozymes due to insufficient endogenous H2O2 and acidity at
tumor sites has always been a conundrum. Herein, an ultrasmall
gold (Au) @
ferrous sulfide (FeS) cascade nanozyme (AuNP@FeS) with H2S-releasing ability constructed with an Au nanoparticle (AuNP) and an FeS nanoparticle (FeSNP) is designed to increase the H2O2 level and acidity in
tumor cells via the collaboration between cascade reactions of AuNP@FeS and the
biological effects of released H2S, achieving enhanced •OH generation as well as effective ferroptosis for
tumor therapy. The cascade reaction in
tumor cells is activated by the
glucose oxidase (GOD)-like activity of AuNP in AuNP@FeS to catalyze intratumoral
glucose into H2O2 and
gluconic acid; meanwhile, the released H2S from AuNP@FeS reduces H2O2 consumption by inhibiting intracellular
catalase (CAT) activity and promotes
lactic acid accumulation. The two pathways synergistically boost H2O2 and acidity in
tumor cells, thus inducing a cascade to generate abundant •OH by catalyzing H2O2 through the POD-like activity of FeS in AuNP@FeS and ultimately causing amplified ferroptosis. In vitro and in vivo experiments demonstrated that AuNP@FeS presents a superior
tumor therapeutic effect compared to that of AuNP or FeS alone. This strategy represents a simple but powerful method to amplify ferroptosis with H2S-releasing cascade nanozymes and will pave a new way for the development of
tumor therapy.