A Bioinspired Nanoprobe with Multilevel Responsive T₁‐Weighted MR Signal‐Amplification Illuminates Ultrasmall Metastases

Abstract Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T₁‐weighted magnetic resonance imaging (MRI) contrast agent, UMFNP‐CREKA is reported. By conjugating the ultrasmall manganese ferrite nanoparticles (UMFNPs) with a tumor‐targeting penta‐peptide CREKA (Cys‐Arg‐Glu‐Lys‐Ala), ultrasmall breast cancer metastases are accurately detected. With a behavior similar to neutrophils' immunosurveillance process for eliminating foreign pathogens, UMFNP‐CREKA exhibits a chemotactic “targeting‐activation” capacity. UMFNP‐CREKA is recruited to the margin of tumor metastases by the binding of CREKA with fibrin‐fibronectin complexes, which are abundant around tumors, and then release of manganese ions (Mn²⁺) to the metastasis in response to pathological parameters (mild acidity and elevated H₂O₂). The localized release of Mn²⁺ and its interaction with proteins affects a marked amplification of T₁‐weighted magnetic resonance (MR) signals. In vivo T₁‐weighted MRI experiments reveal that UMFNP‐CREKA can detect metastases at an unprecedented minimum detection limit of 0.39 mm, which has significantly extended the detection limit of previously reported MRI probe.