Ultrasmall Self-Cascade AuNP@FeS Nanozyme for H₂S-Amplified Ferroptosis Therapy

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.