Tumor-cell nucleus targeting is highly desired for theragnostic nano-prodrugs (NPDs) to enhance cancer diagnostic and therapeutic efficacy as compared to those targeting the cytoplasm or other intracellular organelles. This study presents a well-designed tumor-cell nucleus targeting theragnostic NPD called 177Lu-YNP@FA that can not only deliver bright upconversion/NIR-II fluorescence but also emit radioactive β-ray radiation for efficient tumor fluorescence localization and radionuclide therapy, based on PEGylated folic acid (FA) decorated NaYF4:Yb/Er@NaYF4 core-shell nanocrystals with radionuclide lutetium-177 labeling. Owing to their unique tumor-cell nucleus targeting capacity, the well-designed 177Lu-YNP@FA NPDs can rapidly target the nuclei of Hela cells within eight hours, thereby allowing for the precise localization of two-hundred-micron-sized metastatic tumors of cervical carcinoma, even in the abdominal cavity of a living mouse model, through NIR-II fluorescence imaging. Importantly, these 177Lu-YNP@FA NPDs exhibit superior tumor accumulation (∼24.6%) and retention (∼7.1 days) compared to the NPDs without tumor-cell nucleus targeting ability. This results in highly efficient anticancer outcomes, both in vitro and in vivo, through a pyroptosis-mediated cell death associated with intracellular β-ray radiation of 177Lu radionuclide. These findings have significant implications for the intelligent design of organelle-specific targeting theranostic NPDs, offering new options for diagnosis and treatment in radiopharmaceutical therapy of cancer.