Hydrogen therapy, an emerging therapeutic strategy, has recently attracted much attention in anticancer medicine. Evidence suggests that hydrogen (H₂) can selectively reduce intratumoral overexpressed hydroxyl radicals (•OH) to break the redox homeostasis and thereby lead to redox stress and cell damage. However, the inability to achieve stable hydrogen storage and efficient hydrogen delivery hinders the development of hydrogen therapy. Furthermore, oxygen (O₂) deficiency in the tumor microenvironment (TME) and the electron-hole separation inefficiency in photosensitizers have severely limited the efficacy of photodynamic therapy (PDT). Herein, a smart PdH@MnO₂/Ce6@HA (PHMCH) yolk-shell nanoplatform is designed to surmount these challenges. PdH tetrahedrons combine stable hydrogen storage and high photothermal conversion efficiency of palladium (Pd) nanomaterials with near-infrared-controlled hydrogen release. Subsequently, the narrow bandgap semiconductor manganese dioxide (MnO₂) and the photosensitizer chlorin e6 (Ce6) are introduced into the PHMCH nanoplatform. Upon irradiation, the staggered energy band edges in heterogeneous materials composed of MnO₂ and Ce6 can efficiently facilitate electron-hole separation for increasing singlet oxygen (¹O₂). Moreover, MnO₂ nanoshells generate O₂ in TME for ameliorating hypoxia and further improving O₂-dependent PDT. Finally, the hyaluronic acid-modified PHMCH nanoplatform shows negligible cytotoxicity and selectively targets CD44-overexpressing melanoma cells. The synergistic antitumor performance of the H₂-mediated gas therapy combined with photothermal and enhanced PDT can explore more possibilities for the design of gas-mediated cancer therapy.

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