Transition metal sulfide (TMS) holds great potential in cancer photothermal therapy (PTT) because of the high absorbance in the near-infrared (NIR) region. The short blood circulation time and limited tumor accumulation of TMS-based photothermal agents, however, limit their applications. Herein, we design a novel TMS-based PTT agent, ruthenium sulfide-based nanoclusters (NCs), to overcome the current limitations. We firstly develop a simple method to prepare oleic acid coated ruthenium sulfide nanodots (OA-RuS1.7 NDs) and assemble them into water-soluble NCs via sequentially coating with denatured bovine serum albumin (dBSA) and poly(ethylene glycol) (PEG). The obtained PEG-dBSA-RuS1.7 NCs possess excellent photothermal conversion ability. More significantly, they exhibit enhanced blood circulation time and tumor-targeting efficiency in vivo compared with other TMS-based PTT nanoagents, which may be attributed to their appropriate hydrodynamic diameter (~70 nm) and an ideal charge (~0 mV). These characteristics help the PEG-dBSA-RuS1.7 NCs to escape the removal by the reticuloendothelial system (RES) and kidney. All these advantages enable the PEG-dBSA-RuS1.7 NCs to selectively concentrate in tumor sites and effectively ablate the cancer cells upon NIR irradiation.