Functionalized Holmium‐Doped Hollow Silica Nanospheres for Combined Sonodynamic and Hypoxia‐Activated Therapy

Abstract The oxygen concentration dependence of sonodynamic therapy (SDT) and bioreductive therapy can be utilized to design the strategy of synergistic therapy. Herein, holmium‐doped hollow silica nanospheres are synthesized and then sequentially modified with chlorin e6, carboxyl poly(ethylene glycol) silane, and prostate stem cell antigen (PSCA) monoclonal antibody. The resultant nanocomposite designated as HHSN‐C/P‐mAb has good biocompatibility and can specifically target cancer cells overexpressing PSCA. Due to the inner cavity structure and Ho doping, HHSN‐C/P‐mAb shows high ultrasound (US) imaging contrast capability and excellent high‐field magnetic resonance contrast performance. HHSN‐C/P‐mAb can act as a nanocarrier for loading the bioreductive pro‐drug tirapazamine (TPZ), and the degradation of the hollow nanospheres under the trigger of acidic microenvironment favors the pH responsive release of TPZ from the material. Upon US irradiation, HHSN‐C/P‐mAb produces reactive oxygen species to kill the cancer cells, and importantly, the oxygen consumption during SDT induces an intratumoral hypoxic environment to activate the therapeutic function of codelivered TPZ, resulting in a high‐effective synergistic therapy. The findings of this study highlight that HHSN‐C/P‐mAb is a versatile theranostic nanoplatform for efficient cancer treatment.