The contemporary use of nanomedicines for cancer treatment has been largely limited to serving as carriers for existing therapeutic agents. Here, we provide definitive evidence that, the metallofullerenol nanomaterial Gd@C-82(OH)(22), while essentially not toxic to normal mammary epithelial cells, possesses intrinsic inhibitory activity against triple-negative breast cancer cells. Gd@C-82(OH)(22) blocks epithelial-to-mesenchymal transition with resultant efficient elimination of breast cancer stem cells (CSCs) resulting in abrogation of tumour initiation and metastasis. In normoxic conditions, Gd@C-82(OH)(22) mediates these effects by blocking TGF-alpha signalling. Moreover, under hypoxic conditions found in the tumour micro-environment, cellular uptake of Gd@C-82(OH)(22) is facilitated where it functions as a bi-potent inhibitor of HIF-1 alpha and TGF-beta activities, enhancing CSC elimination. These studies indicate that nanomaterials can be engineered to directly target CSCs. Thus, Gd-metallofullerenol is identified as a kind of non-toxic CSC specific inhibitors with significant therapeutic potential.