Here, cation exchange (CE) reactions are exploited to radiolabel ZnSe, ZnS, and CuFeS 2 metal chalcogenide nanocrystals (NCs) with 64 Cu. The CE protocol requires one simple step, to mix the water-soluble NCs with a 64 Cu solution, in the presence of vitamin C used to reduce Cu(II) to Cu(I). Given the quantitative cation replacement on the NCs, a high radiochemical yield, up to 99%, is reached. Also, provided that there is no free 64 Cu, no purification step is needed, making the protocol easily translatable to the clinic. A unique aspect of the approach is the achievement of an unprecedentedly high specific activity: by exploiting a volumetric CE, the strategy enables to concentrate a large dose of 64 Cu (18.5 MBq) in a small NC dose (0.18 µg), reaching a specific activity of 103 TBq g −1. Finally, the characteristic dielectric resonance peak, still present for the radiolabeled 64 Cu:CuFeS 2 NCs after the partial-CE reaction, enables the generation of heat under clinical laser exposure (1 W cm −2). The synergic toxicity of photo-ablation and 64 Cu ionization is here proven on glioblastoma and epidermoid carcinoma tumor cells, while no intrinsic cytotoxicity is seen from the NC dose employed for these dual experiments.