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When antisense oligomers are intracellular, they migrate to and are retained in the nucleus of tumor cells and therefore may be used to carry Auger electron–emitting radionuclides such as 111In for effective tumor radiotherapy. Methods: Our nanoparticle consists of streptavidin that links 3 biotinylated components: the antiHer2 antibody trastuzumab (to improve pharmacokinetics), the tat peptide (to improve cell membrane transport), and the 111In-labeled antiRIα messenger RNA antisense morpholino (MORF) oligomer. Results: As evidence of unimpaired function, tumor cell and nuclear accumulations were orders of magnitude higher after incubation with 99mTc-MORF/tat/trastuzumab than after incubation with free 99mTc-MORF and significantly higher with the antisense than with the sense MORF. In mice, tumor and normal-tissue accumulations of the 99mTc-MORF/tat/trastuzumab nanoparticle were comparable to those of free 99mTc-trastuzumab, confirming the improved pharmacokinetics due to the trastuzumab component. Although kidneys, liver, and other normal tissues also accumulated the nanoparticle, immunohistochemical evaluation of tissue sections in mice receiving the Cy3-MORF/tat/trastuzumab nanoparticle showed evidence of nuclear accumulation only in tumor tissue. In a dose escalation study, as measured by the surviving fraction, the nanoparticle significantly increased the kill of SK-BR-3 breast cancer Her2+/RIα+ cells, compared with all controls. Conclusion: Significant radiation-induced antisense-mediated cytotoxicity of tumor cells in vitro was achieved using an Auger electron–emitting antisense MORF oligomer administered as a member of a 3-component streptavidin-delivery nanoparticle.