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

Abstract

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.

Nanozymes for the Therapeutic Treatment of Diabetic Foot Ulcers

“…In addition, the released Mn 2+ reacted with H 2 S to generate cytotoxic • OH, which eliminated bacterial infection and accelerated diabetic wound healing. In another study, Zhang et al 212 designed ultrasmall gold@ferrous sulfide cascade nanozyme (AuNP@FeS) synthesized from Au NPs and FeS NPs with H 2 S release capability. Gold nanozymes with GOxlike activity catalyzed the conversion of overexpressed glucose to hydrogen peroxide and gluconic acid, with the potential to promote hydrogen peroxide supply and regulate acidity.…”

Metastable FeSe2 nanosheets as a one-for-all platform for stepwise synergistic tumor therapy

“…Elevated H 2 O 2 levels in tumor cells, compared to normal cells, facilitated the POD-like activity of FeSe 2 NSs, resulting in the generation of cytotoxic ROS. 45,46 Thus, we initially examined the intracellular ROS levels by staining 4T1 cells treated with FeSe 2 NSs using the DCFH-DA probe, along with DAPI staining of the cell nucleus. The CLSM images demonstrated a time-dependent increase in green fluorescence of DCF, indicating a gradual accumulation of ROS within the 4T1 cells (Fig.…”

Depletion and Downregulation of Hydrogen Sulfide Using an Activatable Probe for Promoting Photothermal Therapy toward Colorectal Cancers

“…Moreover, the organic combination of phototherapy with various other diagnostic or treatment methods can make up for the shortcomings of mistargeting effects and adverse effects, − which has received widespread attention. Recently, many reported gas-generating nanoplatforms integrate gas therapy into phototherapy to augment the therapy efficacy and reduce side effects, ,− which finally synergistically realize improvement of treatment effectiveness. For example, some H 2 S-releasing therapy platforms can endow with both delivery ability of hydrogen sulfide and mainline antitumor therapy, such as PTT .…”