Internal radiation therapy (iRT) is an emerging therapeutic approach based on high-energy radionuclide implants categorized as alpha or beta particles placed directly into the tumor to induce cancer cell damage. This work focuses on the development of a unique approach for incorporating β-emitter yttrium-90 (Y) radionuclides via a cation exchange method into lanthanide-based nanoparticles (NPs), consisting of NaLnF composition (Ln = Gd, Lu). The proposed method, thanks to the principle of cation exchange, is a straightforward protocol that involves just the mixing of water-stabilized NPs and radionuclides in aqueous environments at room temperature and, upon a short incubation time, enables the exchange of Gd or Lu ions with Y with high efficiency. The radiotherapeutic effect of cation-exchanged NaLnF:Y is here proven on glioblastoma cell lines with significant cytotoxicity, with the NaLnF:Y NPs, while no intrinsic cytotoxicity was seen for nonradiolabeled NPs at the same material dose. Moreover, in the case of NaGdF NPs, the gadolinium ions functioning as a T contrast agents for magnetic resonance imaging (MRI) enables to track the cation exchange protocol by MR signal enhancement during the ion incorporation: indeed, the Y replacement with Gd enables the release of Gd, which enhances the water exposure of Gd ions and, in turn, the enhancement of the T MRI signal.