Semiconductor nanocrystals, also known as quantum dots, given their robust photoluminescent properties, single source excitation and multicolor emission properties have been employed for multiplexing and long-term imaging studies. [1] On the other hand, cation exchange (CE) reactions consisting of the replacement of cations in the nanocrystalline structure with different metal ions while maintaining in place the anion framework of th nanocrystals, have been extensively used for the synthesis of nanocrystals at different compositions. Here, we exploit CE reactions to radiolabel cadmium-free semiconductor NCs of ZnS, ZnSe and chalcopyrite (CuFeS₂) NCs with Cu-64 radioisotope. [2] We have developed a one-step CE protocol that is straightforward and highly efficient and by tuning the type of ligand coating to be chosen as water soluble stabilizer agents we kept the NC colloidal stability. The amount of Copper-64 to be exchanged could be also tuned in a controlled manner from partial to 100 % cation exchange. This unique approach of CE reaction enables to tune the specific activity in a wide range (from 2 to 100 TBq/g ) with an unprecedentedly record value of specific activity up to 100 TBq/g. This protocol also enables to obtaining ⁶⁴Cu:CuFeS₂ with high radiolabeling yield which do not require any further work out for the purification thus speeding up the radiolabeled NCs preparation. In addition, among the NCs explored, CuFeS₂ NCs even after partial-CE reaction with Copper-64 preserve a plasmonic resonance band, which peaks in the near infrared region making them promising NCs for photo-thermal therapy (PPT). The synergic toxicity of photo-hyperthermia and ⁶⁴Cu mediated radiotherapy ionization here is used to prove the damage to glioblastoma and epidermoid carcinoma tumor cells as demonstrated in vitro on cell culture model. A modified version of this protocol has been also established to obtain sub nanometer copper-64 radio-clusters possessing also radio and photoluminescent properties. Finally, we have also extended the same CE reaction concept to radiolabel lanthanide-based nanoparticles (NPs), consisting of NaLnF4 composition (Ln= Gd, Lu) with Yttrium 90 (⁹⁰Y ). Throughout this presentation, for the best performing materials, preclinical results to evaluate therapeutic efficacy and bio-distribution will be also discussed.