Novel Epigenetics Control (EpC) Nanocarrier for Cancer Therapy Through Dual-Targeting Approach to DNA Methyltransferase and Ten-Eleven Translocation Enzymes

Background/Objectives: Aberrant hypermethylation in the promoter regions of tumor suppressor genes facilitates the pathogenesis and progression of cancer. Therefore, inhibitors targeting DNA methyltransferase (DNMT) have been tested in clinical studies. However, the current monotherapy of DNMT inhibitors shows limited efficacy. Furthermore, the mechanism of action of DNMT inhibitors is DNA replication-dependent. To address these limitations, we developed a novel core–shell-type “epigenetics control (EpC) nanocarrier” that encapsulated decitabine (5-aza-dC) in the PLGA core nanoparticle and hybridized TET1 gene-encoding pDNA on the lipid shell surface. This study aimed to evaluate whether the dual delivery of DNMT inhibitors and pDNA of TET1 could synergistically enhance tumor suppressor gene expression and induce cell cycle arrest and/or apoptosis in cancer cells. Herein, we demonstrate the potential of the EpC carrier in HCT116 human colon cancer cells to upregulate tumor suppressor gene expression and rapidly achieve cell cycle arrest. Methods: PLGA core nanoparticles were prepared by the W/O/W double emulsion method. The formation of core–shell nanoparticles and complexation with pDNA were investigated and optimized by dynamic light scattering, zeta potential measurement, and agarose gel electrophoresis. The cellular uptake and transfection efficiency were measured by confocal laser scanning microscopy and a luciferase assay, respectively. The expression of p53 protein was detected by Western blotting. The anti-tumor effects of the EpC nanocarrier were evaluated by cell cycle analysis and an apoptosis assay. Results: The EpC nanocarrier delivered the DNMT inhibitor and TET gene-encoding pDNA into HCT116 cells. It promoted the expression of the tumor suppressor protein p53 and induced rapid cell cycle arrest in the G2/M phase in HCT116 cells. Conclusions: Our findings suggest that the dual-targeting of DNMT and TET enzymes effectively repairs aberrant DNA methylation and induces growth arrest in cancer cells, and the dual-targeting strategy may contribute to the advancement of epigenetic cancer therapy.