Smart Telomerase-Gated DNA cage for precise siRNA release in cancer cells

Abstract

Oligonucleotide nanoparticles (ONPs) have been utilized as a small interfering RNA (siRNA) delivery system because of their multiple advantages. However, the release of siRNA by ONPs inner cells mainly relies on acidic environments and high concentrations of ATP. These conditions do not allow the specific release of siRNA in tumor cells, which would prevent the side effects that result from the release of siRNA in normal cells. In this study, a prism oligonucleotide nanoparticle (pONP)-based delivery system was designed, which targeted with telomeric primers (TS) that can be extended by cancer-specific telomerase for specifically releasing siRNA inside telomerase-positive cancer cells. In vitro tests confirmed that this cage facilitated the release of siRNA specifically into telomerase-positive HeLa and MDA-MB-231 tumor cells. The release was so precise that almost no siRNA was released into telomerase-negative cells. In vivo tests also confirmed that this cage could release sibcl-2 specifically in tumor cells in an MDA-MB-231 orthotopic breast cancer mouse model. Moreover, the cage has a long half-life (e.g., 2.83 h in FBS) in the circulatory system and protects the cargo from nuclease degradation; thus, the released sibcl-2 effectively silences the translation of target cancer-related mRNA (bcl-2), similar to the sibcl-2 delivered by Lipo6000 in the telomerase-positive environment of cancer cells. pONP/TS/siRNA is readily prepared using a simple sequence design together with one-step self-assembly. This nanoparticle cage is a promising delivery method for precise siRNA release into targeted telomerase-positive cancer cells.