Gas Empowered Dual‐Cascade Strategy for Augmented Single‐Atom Nanotherapies

Abstract Single‐atom nanotherapies have received numerous attention in malignant oncotherapy. 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‐cascade synergistic treatment strategy is demonstrated with domino effect, which can sequentially reinforce single‐atom nanozyme (SAzyme)‐based enzymatic therapeutics and mild photothermal therapy (PTT) (< 45 °C). In the proof‐of‐concept study, Fe single atom nanozyme (Fe/SAzyme) loaded with hydrogen sulfide (H 2 S) donor NaHS is developed for HSPs‐silencing mediated mild PTT. The generated H 2 S suppresses the catalase activity to achieve “intracellular H 2 O 2 conservation”, thereby furnishing the enzyme substrate to Fe/SAzyme to produce abundant cytotoxic hydroxyl radicals (·OH) for augmented enzymatic therapeutics. Then, excess ·OH 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‐triggered dual‐cascade strategy achieves domino H 2 S/·OH/mitochondrial dysfunction synergistic effect, endowing SAzymes with maximum antitumor efficacy via enzymatic therapeutics combined with mild PTT. This dual‐cascaded gas/enzymatic/mild PTT synergistic oncotherapy not only exhibits a new pathway for gas‐facilitated mild PTT, but also offers a valuable paradigm for the application of “1 + 1 + 1 > 3” multimodal synergistic tumor therapy.