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The identification of metastasis "seeds," isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for noninvasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T 2 -decaying effects under UHF conditions, which compromises T 1 MRI capability and further impedes the precise imaging of small lesions. Herein, this study reports a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost nonmagnetic. This unique characteristic effectively mitigates T 2 -decaying effect while concurrently enhancing UHF T 1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r 2 /r 1 value (≈1.06), enabling noninvasive visualization of ITCs with an exceptional detection threshold of ≈0.16 mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research., (© 2024 Wiley‐VCH GmbH.)

Bimetallic iron-noble metal alloy nanoparticles have emerged as promising contrast agents for magnetic resonance imaging (MRI) due to their biocompatibility and facile control over the element distribution. However, the inherent surface energy discrepancy between iron and noble metal often leads to Fe atom segregation within the nanoparticle, resulting in limited iron-water molecule interactions and, consequently, diminished relaxometric performance. In this study, we present the development of a class of ligand-induced atomically segregation-tunable alloy nanoprobes (STAN) composed of bimetallic iron-gold nanoparticles. By manipulating the oxidation state of Fe on the particle surface through varying molar ratios of oleic acid and oleylamine ligands, we successfully achieve surface Fe enrichment. Under the application of a 9 T MRI system, the optimized STAN formulation, characterized by a surface Fe content of 60.1 at %, exhibits an impressive r 1 value of 2.28 mM -1 ·s -1 , along with a low r 2/ r 1 ratio of 6.2. This exceptional performance allows for the clear visualization of hepatic tumors as small as 0.7 mm in diameter in vivo , highlighting the immense potential of STAN as a next-generation contrast agent for highly sensitive MR imaging.

Ultra-high-field (UHF) magnetic resonance imaging (MRI) stands as a pivotal cornerstone in biomedical imaging, yet the challenge of false imaging persists, constraining its full potential. Despite the development of dual-mode contrast agents improving conventional MRI, their effectiveness in UHF remains suboptimal due to the high magnetic moment, resulting in diminished T1 relaxivity and excessively enhanced T2 relaxivity. Herein, we report a DNA-mediated magnetic-dimer assembly (DMA) of iron oxide nanoparticles that harnesses UHF-tailored nanomagnetism for fault-free UHF-MRI. DMA exhibits a dually enhanced longitudinal relaxivity of 4.42 mM -1 ·s -1 and transverse relaxivity of 26.23 mM -1 ·s -1 at 9 T, demonstrating a typical T1-T2 dual-mode UHF-MRI contrast agent. Importantly, DMA leverages T1-T2 dual-modality image fusion to achieve artifact-free breast cancer visualization, effectively filtering interference from hundred-micrometer-level false-positive signals with unprecedented precision. The UHF-tailored T1-T2 dual-mode DMA contrast agents hold promise for elevating the accuracy of MR imaging in disease diagnosis.

Histopathological level imaging in a non-invasive manner is important for clinical diagnosis, which has been a tremendous challenge for current imaging modalities. Recent development of ultra-high-field (UHF) magnetic resonance imaging (MRI) represents a large step toward this goal. Nevertheless, there is a lack of proper contrast agents that can provide superior imaging sensitivity at UHF for disease detection, because conventional contrast agents generally induce T2 decaying effects that are too strong and thus limit the imaging performance. Herein, by rationally engineering the size, spin alignment, and magnetic moment of the nanoparticles, we develop an UHF MRI-tailored ultra-sensitive antiferromagnetic nanoparticle probe (AFNP), which possesses exceptionally small magnetisation to minimize T2 decaying effect. Under the applied magnetic field of 9 T with mice dedicated hardware, the nanoprobe exhibits the ultralow r 2 /r 1 value (~1.93), enabling the sensitive detection of microscopic primary tumours (<0.60 mm) and micrometastases (down to 0.20 mm) in mice. The sensitivity and accuracy of AFNP-enhanced UHF MRI are comparable to those of the histopathological examination, enabling the development of non-invasive visualization of previously undetectable biological entities critical to medical diagnosis and therapy.

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r 1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.

Ultra‐high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low‐field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand‐mediated magnetism‐conversion nanoprobe (MCNP) composed of 3‐mercaptopropionic acid ligand‐coated silver‐gadolinium bimetallic nanoparticles. The MCNP exhibits a pH‐dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH‐activatable UHF MRI. Under neutral pH, the thiolate (−S−) ligands lead to short τ′m and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (−SH) ligands, resulting in prolonged τ′m and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH‐sensitive changes in Ag−S binding affinity of the MCNP lead to a remarkable (>10‐fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next‐generation UHF‐tailored smart MRI contrast agent. [ABSTRACT FROM AUTHOR]