Sequence-Programmable Iron Oxide Nanoparticles Enable Dual-Phase T₁-Weighted MRI of Ultrasmall Hepatocellular...

Early-stage hepatocellular carcinoma diagnosis is hindered by the inability of conventional MRI to concurrently detect tiny tumors and delineate their microvascular networks. To address this, we engineered sequence-programmable iron oxide nanoparticles with precisely tuned magnetic properties that enable dual-phase T₁-weighted imaging tailored to specific MRI sequences. Under ultra-short TR/TE angiography sequences, these nanoparticles produce strong T₁-positive enhancement, allowing high-resolution visualization of tumor neovasculature down to 0.3 mm (in rabbits) at one-quarter of the standard gadolinium dose. Following selective uptake and aggregation by Kupffer cells, the same nanoparticles induce localized magnetic field inhomogeneity, generating pronounced T₁-negative contrast in normal liver parenchyma on conventional sequences and thereby highlighting HCC lesions independent of OATP expression with detection sensitivity down to 0.4 mm (in mouse). This single-agent, dual-phase strategy integrates sensitive lesion detection with detailed vascular phenotyping, and is enabled by a green, scalable synthesis using an FDA-approved biocompatible polymer. By overcoming key limitations of current gadolinium-based agents, our platform provides a versatile and high-performance imaging solution for comprehensive early-stage HCC evaluation.