A Bioinspired Nanoprobe with Multilevel Responsive <i>T</i>₁‐Weighted MR Signal‐Amplification Illuminates Ultrasmall Metastases

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 H2 O2 ). 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.