Glypican-3-targeted bioconjugates for hepatocellular carcinoma: design, engineering, and translational applications.

Hepatocellular carcinoma (HCC) is among the most prevalent malignancies and remains a leading cause of cancer-related mortality worldwide. Because early-stage HCC often has a silent clinical course and current surveillance strategies remain imperfect, many patients with HCC are diagnosed at an intermediate or advanced stage. In addition, the high rates of recurrence and metastasis contribute to the persistently poor overall prognosis. Glypican-3 (GPC3) is minimally expressed in normal adult liver tissue, but is frequently upregulated in HCC. However, several major barriers remain, including intratumoral expression heterogeneity, the challenge of achieving stable delivery under conditions of high intrahepatic background, and the lack of robust clinical evidence supporting combined diagnostic and therapeutic strategies. In this review, we summarize the biological basis of GPC3 and recent advances in its application in HCC, with particular emphasis on the development of multiple targeting platforms, including peptides, single-chain variable fragments (scFvs), nanobodies, and full-length antibodies. Our translational decision framework evaluates these platforms not only by absolute tumor uptake but also by tumor-to-liver (T/L) ratio, tumor retention, organ dosimetry, conjugation homogeneity, and manufacturability. Looking ahead, GPC3 molecular imaging may support patient selection, treatment planning, and the evidence-based optimization of combination strategies. GPC3-targeting bioconjugate platforms include four types: GPC3-binding peptide, anti-GPC3 nanobody, anti-GPC3 single-chain variable fragment, and anti-GPC3 monoclonal antibody. These platforms integrate with other diagnostics and therapeutic modalities such as PET/CT imaging, radioligand therapy, immune checkpoint inhibitors targeting PD-1/PD-L1, tyrosine kinase inhibitors including sorafenib and lenvatinib, and chemotherapy or immunotherapy.