Iron oxide nanoparticles for hepatocellular carcinoma theranostics: From nanoplatform design to clinical translation

The challenges in early diagnosis and effective treatment of hepatocellular carcinoma (HCC) are largely attributable to the underlying cirrhosis, impaired hepatic reserve, and the added complexity of heterogeneous tumor vascularity in many patients. Iron oxide nanoparticles (IONPs) are promising platforms for HCC diagnosis and treatment because of their magnetic properties, tunable magnetic resonance imaging (MRI) contrast, magnetothermal conversion capability, and modifiable surface chemistry. These features enable IONPs to be used for image-guided diagnosis, liver-directed locoregional therapy, systemic drug delivery, and treatment monitoring. In this review, we summarize the composition, crystal structure, size-dependent magnetic properties, surface modification, and in vivo fate of IONPs, along with how these characteristics influence their performance in HCC imaging and therapy. For diagnostic applications, we focus on passive accumulation, particularly mononuclear phagocyte system (MPS)-mediated hepatic contrast, ligand-mediated active targeting, and multimodal imaging. We then review therapeutic strategies, including magnetic hyperthermia (MHT), stimuli-responsive drug delivery, and combination therapy. Major barriers to clinical translation are also addressed, encompassing the heterogeneous enhanced permeability and retention (EPR) effect, high background uptake by non-tumoral liver tissue, liver function-related safety concerns, limitations of alternating magnetic fields, and manufacturing reproducibility.