Sequence‐Programmable Iron Oxide Nanoparticles Enable Dual‐Phase T 1 ‐Weighted MRI of Ultrasmall Hepatocellular Carcinoma and Tumor Vascular Architecture

ABSTRACT 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 T 1 ‐weighted imaging tailored to specific MRI sequences. Under ultra‐short TR/TE angiography sequences, these nanoparticles produce strong T 1 ‐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 T 1 ‐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.