The strategy of drug encapsulation with biocompatible polymeric nanocapsules could be a promising approach to improve the delivery of poorly water-soluble drugs for cancer therapy. The aim of this study was to investigate the drug delivery of tamoxifen from biocompatible nanocapsules made of poly (D,L-lactide) (PLA) c o r e a n d 1 , 2 -d i p a l m i t o y l -s n -g l y c e r o -3phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DPPE-PEG) shell in the treatment of breast cancer.The analytical techniques such as FTIR, XRD, SEM, and TEM were used to investigate the structure of nanocapsules. Tamoxifen drug encapsulation efficiency and loading percentages as well as release kinetics at different pH values and temperatures were used to confirm the appropriate performance of these novel nanocapsules. The maximum tamoxifen release occurred at 40°C, pH = 4. Based on the SEM and TEM images, the sizes of nanocapsules were between 57 and 159 nm. In order to investigate the anticancer effects and cytotoxicity of encapsulated tamoxifen in PLA/DPPE-PEG nanocapsules, the tetrazolium-based colorimetric (MTT) assay and cell cycle arrest analysis on MCF-7 breast cancer cell were performed. Also, cell cycle-related gene expressions of p53 and p21 in treated MCF-7 cells with tamoxifen-loaded PLA/DPPE-PEG nanocapsules were evaluated. The results of MTT cell proliferation experiments exhibited an increase in the cytotoxicity of tamoxifen nanocapsules on MCF-7 cell line compared with free tamoxifen. The 1.2-fold increase in the G1 stage compared with the control group in the cell cycle arrest protocol as well as the notable overexpression of p53 and p21 genes suggested that these nanocapsules arrested cell cycle in MCF-7 cells.