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This study aimed at investigating the potential mechanism of improved transportation of the curcumin loaded D-α-tocopherol polyethylene glycol 1000 succinate coated nanodiamonds system (NDs/CUR/TPGS complexes) using an in vitro Caco-2 cell monolayer model. The core–shell structured NDs/CUR/TPGS nanocomplexes were 196.32 ± 5.76 nm in size, with a high loading efficiency of 81.59 ± 3.42%. Cytotoxicity results suggested that the blank NDs did not induce any serious toxicity on Caco-2 cells even after incubated for 72 h. The cell viability for all the series of CUR loaded preparations was found to follow the sequence of CUR suspension > NDs/CUR > NDs/CUR/TPGS. Confocal laser fluorescence microscopy (CLSM) and flow cytometry system (FACS) studies confirmed that the cellular uptake of NDs could be efficiently enhanced by TPGS decoration. The transport mechanism of NDs/CUR and TPGS coated ones was mainly through an energy dependent, clathrin-mediated and caveolin-mediated endocytosis, and the endocytosis of NDs/CUR was also via macropinocytosis. Furthermore, the Papp value (AP-BL) of NDs/CUR and NDs/CUR/TPGS was 2.09- and 3.86-fold higher than that of the CUR suspension. All the results demonstrated that the pharmacological activates and intestinal permeability of CUR across Caco-2 cell monolayer was greatly enhanced by NDs/CUR/TPGS nanocomplexes. Thus NDs could be a promising oral drug delivery platform for improving the intestinal permeability and oral bioavailability of poorly soluble drugs.