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However, the insufficient enzyme substrate and the upregulation of heat shock proteins during therapeutic interventions are seldom concurrently noticed. Herein, a novel gas empowered dual\u2010cascade synergistic treatment strategy is demonstrated with domino effect, which can sequentially reinforce single\u2010atom nanozyme (SAzyme)\u2010based enzymatic therapeutics and mild photothermal therapy (PTT) (&lt; 45 \u00b0C). In the proof\u2010of\u2010concept study, Fe single atom nanozyme (Fe\/SAzyme) loaded with hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) donor NaHS is developed for HSPs\u2010silencing mediated mild PTT. The generated H<jats:sub>2<\/jats:sub>S suppresses the catalase activity to achieve \u201cintracellular H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> conservation\u201d, thereby furnishing the enzyme substrate to Fe\/SAzyme to produce abundant cytotoxic hydroxyl radicals (\u00b7OH) for augmented enzymatic therapeutics. Then, excess \u00b7OH induced mitochondrial dysfunction blocks adenosine triphosphate (ATP) energy supply to realize cellular energy remodeling, which hinders overexpression of HSPs and enhances mild PTT of Fe\/SAzyme both in vitro and vivo. Consequently, the gas\u2010triggered dual\u2010cascade strategy achieves domino H<jats:sub>2<\/jats:sub>S\/\u00b7OH\/mitochondrial dysfunction synergistic effect, endowing SAzymes with maximum antitumor efficacy via enzymatic therapeutics combined with mild PTT. This dual\u2010cascaded gas\/enzymatic\/mild PTT synergistic oncotherapy not only exhibits a new pathway for gas\u2010facilitated mild PTT, but also offers a valuable paradigm for the application of \u201c1\u00a0+\u00a01\u00a0+\u00a01\u00a0&gt;\u00a03\u201d multimodal synergistic tumor therapy.<\/jats:p>","DOI":"10.1002\/adhm.202404001","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:10:47Z","timestamp":1733098247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Gas Empowered Dual\u2010Cascade Strategy for Augmented Single\u2010Atom Nanotherapies"],"prefix":"10.1002","volume":"14","author":[{"given":"Yong","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical Engineering Nanjing University  Nanjing 210023 P. R. 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