The clinical applications of a large variety of inorganic nanomaterials have been severely limited by their long-term retention with potential toxicity in the body. Herein, we develop a self-guided photothermal nanocarrier based on MoS2 nanodots (MoS2 NDs) modified with copolymer P(OEGA-co-VBA) and targeting ligands of transferrin (Tf). The copolymer P(OEGA-co-VBA) is synthesized via RAFT polymerization and not only utilized to improve the biocompatibility of MoS2 NDs, but also efficiently load the drug doxorubicin (DOX) via acid-cleavable Schiff base bonds. Besides, thiol functionalized transferrin (Tf-SH) is anchored onto the surface of MoS2 NDs via the formation of disulfide bonds, which could further enhance the cellular engulfed of MoS2 NDs nanocarrier to HepG(2) cells. The as-prepared nanocarrier is stable in physiological condition while quickly release drug upon the synergistic trigger of acidic pH and glutathione (GSH). Moreover, the modified MoS2 (DOX-POVMoS2-Tf) nanoagents shows better therapeutic effect probably attributed to the synergistic effects of targeted uptake, pH, GSH and NIR induced localized heating, which suggest the designed MoS2 nanocarrier is promising for applications in multi-modal biomedical therapy.