An Oxidative Stress Nano‐Amplifier for Improved Tumor Elimination and Combined Immunotherapy

Abstract Amplifying oxidative stress to disrupt intracellular redox homeostasis can accelerate tumor cell death. In this work, an oxidative stress amplifier (PP@T) is prepared for enhanced tumor oxidation therapy to reduce tumor growth and metastases. The nano‐amplifier has been successfully constructed by embedding MTH1 inhibitor (TH588) in the PDA‐coated porphyrin metal–organic framework PCN‐224. The controllable‐released TH588 is demonstrated from pores can hinder MTH1‐mediated damage‐repairing process by preventing the hydrolysis of 8‐oxo‐dG, thereby amplifying oxidative stress and exacerbating the oxidative DNA damage induced by the sonodynamic therapy of PP@T under ultrasound irradiation. Furthermore, PP@T can effectively induce immunogenic cell death to trigger systemic anti‐tumor immune response. When administered in combination with immune checkpoint blockade, PP@T not only impedes the progression of the primary tumor but also achieves obvious antimetastasis in breast cancer murine models, including orthotopic and artificial whole‐body metastasis models. Furthermore, the nanoplatform also provides photoacoustic imaging for in vivo treatment guidance. In conclusion, by amplifying oxidative stress and reactive oxygen species sensitized immunotherapy, this image‐guided nanosystem shows potential for highly specific, effective combined therapy against tumor cells with negligible side‐effects to normal cells which will provide a new insight for precise tumor treatment.