Targeted Magnetic Resonance Imaging/Near‐Infrared Dual‐Modal Imaging and Ferroptosis/Starvation Therapy of Gastric Cancer with Peritoneal Metastasis

Abstract Accurate identification and visualization of peritoneal metastases (PM) are clinically essential to improving the prognosis for gastric cancer. However, owing to the multifocal spread of peritoneal metastasis nodules, small size, and close contact with adjacent organs, identifying and completely removing them during surgery is extremely challenging, resulting in cancer treatment failure and recurrence. This study develops a T₁‐weighted magnetic resonance imaging (MRI) contrast agent (FeGdNP)‐loaded indocyanine green/glucose oxidase (ICG/GOx) with conjugation of an RGD dimer (RGD2) and acid‐labile polymer mPEG (FeGdNP‐ICG/GOx‐RGD2‐mPEG). Compared with commercial Magnevist, the proposed FeGdNP‐ICG/GOx‐RGD2‐mPEG shows a two to three‐fold higher tumor ΔSNR in MRI of peritoneal metastasis and subcutaneous animal models. Compared with free ICG, the increased fluorescent signal of FeGdNP‐ICG/GOx‐RGD2‐mPEG allows for the detection of tiny tumor metastatic nodules (<3 mm), and the removal of the peritoneum transplanted tumors. Abundant gluconic acid and H₂O₂ are generated during the GOx‐mediated glucose depletion process in cancer cells, thereby enhancing Fenton reaction efficiency. Accumulated toxic ·OH can damage the mitochondrial function and induce the release of mitochondrial reactive oxygen species, which activates the ferroptosis pathway. The data indicate the potential of the nanoparticles for MRI preoperative diagnosis, intraoperative fluorescence‐guided navigation, and ferroptosis tumor therapy.