Zirconia‐Platinum Nanohybrids for Ultrasound‐Activated Sonodynamic‐Thermodynamic Bimodal Therapy by Inducing Intense Intracellular Oxidative Stress

Abstract The therapeutic exploration of nano‐zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano‐sonosensitizer of ZrO_2−x@Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen‐deficient ZrO_2−x. Compared to 3.09 eV of nano‐ZrO_2−x, the bandgap of ZrO_2−x@Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e⁻/h⁺ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (¹O₂) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase‐mimic activity can promote ¹O₂ generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH), US‐stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (^•R). US‐triggered reactive oxygen species generation and hyperthermia‐induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic‐thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof‐of‐concept paradigm expands the medical use of nano‐zirconia and provides useful insights for its therapeutic perspectives.