Glycogen for Smyd3-antisense oligonucleotide delivery and enhanced liver cancer gene therapy

Abstract

The overexpression of Smyd3 is closely related to the progression of various cancers. Smyd3 is overexpressed in liver cancers but is hardly detectable in normal tissues; consequently, it is attracting increasing attention as a target for liver cancer therapy. Therefore, silencing Smyd3 mRNA using antisense oligonucleotides (ASOs) offers a promising option for liver cancer therapy. However, their clinical application is hindered by their poor stability and cellular uptake. Although promising, strategies such as chemical modification of the ASOs as well as the synthetic nanocarriers raise safety concerns. The efficient delivery of ASOs into tumor cells remains a big challenge. In this study, we developed a novel glyco-nanovector for Smyd3-ASO delivery. Glycogen possesses an inherent dendritic nanostructure. Aminated glycogen (NG) was simply synthesized by grafting glycogen with diethylenetriamine (DETA). NG possessed good biocompatibility. Cationic NG efficiently formed a complex with Smyd3-ASOs and shielded them from enzymatic degradation. NG significantly enhanced the cellular uptake of Smyd3-ASOs in HepG2 cells. As a result, NG/ASOs decreased the translation of Smyd3 proteins from mRNA and thus inhibited the proliferation of HepG2 cells. This study underscores the potential of glycogen as an efficient nanovector for ASO delivery and cancer gene therapy.