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

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 degrees C). In the proof-of-concept study, Fe single atom nanozyme (Fe/SAzyme) loaded with hydrogen sulfide (H2S) donor NaHS is developed for HSPs-silencing mediated mild PTT. The generated H2S suppresses the catalase activity to achieve "intracellular H2O2 conservation", thereby furnishing the enzyme substrate to Fe/SAzyme to produce abundant cytotoxic hydroxyl radicals (<middle dot>OH) for augmented enzymatic therapeutics. Then, excess <middle dot>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 H2S/<middle dot>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.