Nanobodies have been developed rapidly as targeted probes for molecular imaging owing to their high affinity, outstanding tissue penetration, and rapid blood clearance. However, the short retention time at the tumor site limits their application in targeted radionuclide therapy. In this study, we designed a dual-targeting nanobody referred to as MIRC213-709, which can specifically bind to the HER2 receptor in tumor cell lines with high affinity (by nanobody MIRC213) and endogenous IgG in plasma to prolong the half-life by the MIRC213 C-terminal fusion nanobody, MIRC709. The nanobodies were site-specifically radiolabeled with 99m Tc and 177 Lu, and radiochemical purity was >95% after purification. The long blood circulation time and tumor retention property of 99m Tc/ 177 Lu-MIRC213-709 were confirmed by a blood clearance assay, single-photon emission computed tomography (SPECT), and a biodistribution study. The blood clearance assay showed that the distribution phase half-life ( T 1/2α ) and elimination phase half-life ( T 1/2β ) of 99m Tc-MIRC213-709 were 6.74- and 19.04-fold longer than those of 99m Tc-MIRC213, respectively. The SPECT/CT and biodistribution results showed that the highest uptake of 177 Lu-MIRC213 in the NCI-N87 model was 5.24 ± 0.95% ID/g at 6 h p.i., while the highest uptake of 177 Lu-MIRC213-709 in the NCI-N87 model was 30.82 ± 7.29% ID/g at 48 h p.i. Compared with 177 Lu-MIRC213, 177 Lu-MIRC213-709 had a 16.9-fold increased tumor cumulative uptake (2606 ± 195.1 vs 153.9 ± 22.37% ID/g·h). The targeted radionuclide therapy assay was performed in the NCI-N87 tumor model, and treatment monitoring ended on day 32. The post-treatment/pretreatment tumor volumes were 12.99 ± 1.66, 3.58 ± 0.96, 1.26 ± 0.17, and 1.54 ± 0.50 in the 0, 9, and 18 MBq single-dose groups and the two 9 MBq divided dose group (14 days apart), respectively. All treatment groups showed significant therapeutic effects ( P < 0.0001). Thus, fusion with the IgG-binding nanobody MIRC709 provides MIRC213 derivatives with improved metabolic properties for targeted radionuclide therapy.