*4.4. Nanobody-Based Probes*

A single-domain antibody (sdAb, nanobody) is an engineered antibody fragment containing a single monomeric variable antibody domain. Compared to the large size of full-size antibodies (~150 kDa), nanobodies (~15 kDa) can be delivered to tumors with comparatively less obstruction [141]. Nanobodies can be reconstructed to Fc-domains or conjugated to molecular inhibitors, radioisotopes, fluorescent dye, and nanoparticles, making them suitable for targeting tumors with many applications [142]. For example, Jailkhani et al. established nanobody libraries against extracellular matrix (ECM) proteins, which are hallmarks of many diseases, including cancers. PET/CT imaging showed that 64Cu-labeled NJB2 nanobody probes targeted ECM and detected breast cancer and melanoma *for* primary and metastatic foci (including thyroid) with excellent contrast [143]. Thus, nanobody probes may open up a promising opportunity for application in TCs. So far, nanobody probes remain absent in TC research [144]. Our team has developed a series of nanobodies targeting various targets (e.g., tumor-associated calcium signal transducer 2 [TACSTD2, TROP-2], ICAM-1, integrin associated protein [CD47], and melanoma cell adhesion molecule [MCAM, CD146]) and are fully exploring the theranostic potential of the nanobodies in TCs.
