Significance Although many efforts have been devoted to localize and monitor cancer progression, it is still difficult to precisely evaluate the development of cancers for efficient targeted treatments. Herein, we demonstrate a straightforward strategy using in situ self-assembly of gold nanocluster–DNA complexes. In combination with the tumor suppressor gene-phosphatase and tensin homolog (PTEN), the gold nanocluster-PTEN complexes could realize targeted bioimaging and identification of cancers and simultaneously inhibit the effect of relevant oncogenes. Meanwhile, these biocompatible self-assembling gold nanocluster–PTEN complexes cannot only facilitate safe and targeted therapeutics, but can also avoid the side effects of conventional DNA transfection. This strategy allows the possibility of establishing a multimode platform for accurately targeted cancer theranostics to eradicate tumors and vascularized metastases.