Convenient therapeutic protocols against hepatocellular carcinoma (HCC) exhibit low treatment effectiveness, especially in the context of long-term effects, which is primarily related to late diagnosis and high tumor heterogeneity. Current trends in medicine concern combined therapy to achieve new powerful tools against the most aggressive diseases. When designing modern, multimodal therapeutics, it is necessary to look for alternative routes of specific drug delivery to the cell, its selective (with respect to the tumor) activity and multidirectional action, enhancing the therapeutic effect. Targeting the physiology of the tumor makes it possible to take advantage of certain characteristic properties of the tumor that differentiate it from other cells. In the present paper we designed for the first time iodine-125 labeled platinum nanoparticles for combined “chemo-Auger electron” therapy of hepatocellular carcinoma. High selectivity achieved by targeting the tumor microenvironment of these cells was associated with effective radionuclide desorption in the presence of H2O2. The therapeutic effect was found to be correlated with cell damage at various molecular levels including DNA DSBs and was observed in a dose-dependent manner. A three-dimensional tumor spheroid revealed successful radioconjugate anticancer activity with a significant treatment response. A possible concept for clinical application after priorin vivotrials may be achievedviatransarterial injection of micrometer range lipiodol emulsions with encapsulated125I-NP. Ethiodized oil gives several advantages especially for HCC treatment; thus bearing in mind a suitable particle size for embolization, the obtained results highlight the exciting prospects for the development of PtNP-based combined therapy.