Automatic-degradable Mo-doped W₁₈O₄₉ based nanotheranostics for CT/FL imaging guided synergistic chemo/photothermal/chemodynamic therapy

The development of nanotherapeutics that can efficiently inhibit tumors and rapidly degrade in both cured and healthy tissues remains a research imperative. Herein, we developed tumor microenvironment (TME)-responsive Mo-doped W₁₈O₄₉ nanobundles (MoWO NBs), which are co-assembled hyaluronic acid (HA) and doxorubicin (DOX) to achieve CT/FL imaging-guided multimodal cancer therapy. MoWO NBs exhibit multiple merits: (1) MoWO NBs degrade rapidly in the normal physiological environment but slowly in the weakly acidic TME, which leads to the selective accumulation of MoWO NBs at tumor sites and can prolong the therapeutic effect. (2) The existing Mo⁴⁺ and W⁵⁺ ions in MoWO NBs bestow the NBs with Fenton-like reaction activity to generate cytotoxic hydroxyl radicals (OH) from endogenous H₂O₂. Meanwhile, overexpressed glutathione (GSH) can reduce Mo⁶⁺ and W⁶⁺ ions in MoWO NBs to lower valence states, further enhancing the chemodynamic activity of MoWO NBs. (3) Under NIR-II laser irradiation, MoWO with a photothermal conversion efficiency of 45.5% could trigger powerful photothermal therapeutic effects in vitro and in vivo. (4) Owing to the fluorescence emission of DOX and the high Z-elements of molybdenum and tungsten, fluorescence (FL) imaging and computed tomography (CT) imaging have the potential to be used to monitor the biodistribution of Mo-W₁₈O₄₉@DOX@HA (MoWODH) in vivo. More importantly, the synergistic Chemo/PTT/CDT of MoWODH NCs greatly inhibited tumor growth. This work may broaden the path for smart nanomaterials and TME-responsive therapies.