Constructing ¹⁷⁷ Lu-Labeled Lanthanide Nano-Radiopharmaceuticals for Efficient Postoperative Tumor Radionuclide Therapy and Prognosis Monitoring

Cancer remains a global health challenge, with current postoperative adjuvant therapies for advanced solid tumors being limited by therapeutic resistance, off-target effects, and insufficient treatment monitoring. Here, we report a rational design of a novel tumor-targeted ¹⁷⁷Lu-labeled lanthanide nanoradiopharmaceutical called ¹⁷⁷Lu-LnNRP@HER2 (namely, NaGdF₄:Yb@NaErF₄:Tm@NaYF₄:Yb/¹⁷⁷Lu@NaYF₄@DSPE-PEG-HER2). This nanoradiopharmaceutical is engineered to enable precision postoperative β-radiotherapy in combination with real-time radiation-free prognosis monitoring. The unique multilayer structure of ¹⁷⁷Lu-LnNRP@HER2 simultaneously facilitates tumor-selective β-particle irradiation through stably labeled ¹⁷⁷Lu for eliminating residual tumor cells and provides strong upconversion/near-infrared-II (UC/NIR-II) fluorescent signals for intraoperative tumor margin delineation and postoperative monitoring. In an orthotopic gastric tumor model, ¹⁷⁷Lu-LnNRP@HER2 demonstrates significant postoperative therapeutic efficacy and real-time prognosis monitoring capability, achieving an 84% suppression of recurrence, an 88.6% reduction in metastasis, and a 2.6-fold increase in median survival. Multimodal analyses, including high-resolution cell imaging, flow cytometry, and transcriptomics, reveal that the excellent antitumor activity of ¹⁷⁷Lu-LnNRP@HER2 is mainly attributed to the DNA damage and reactive oxygen species elevation arising from the proximity-targeted β-particle irradiation of tumor cell nuclei and mitochondria. These findings address a key gap in the field by synchronizing targeted radionuclide therapy with integrated real-time monitoring, thus promising a new paradigm for precision oncology.