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.