Glycyrrhetinic Acid-Grafted Glycogen Nanoparticles Mediated Hepatic Delivery of Survivin Antisense Oligonucleotides for Liver Cancer-Targeted Gene Therapy.

As an apoptosis inhibitor, survivin has become a highly promising cancer target due to its overexpression in most tumors and its near absence in normal tissues. While antisense oligonucleotides (ASOs) targeting survivin mRNA represent a promising therapeutic approach for liver cancer, their clinical translation is significantly hampered by critical challenges such as rapid enzymatic degradation, poor cellular internalization, and off-target tissue distribution. Although strategies such as chemical modification of ASO and the use of synthetic nanocarriers show promise, they also raise safety issues. Effectively delivering ASO into tumor cells still poses a significant challenge. Herein, we engineered an innovative glyco-nanovector aimed at the hepatic delivery of survivin ASO, with the goal of advancing gene therapy strategies for liver cancer. Glycogen was first aminated (NG) and subsequently chemically modified with glycyrrhetinic acid (GA). GA is a ligand targeting the GA receptors that are overexpressed in hepatocellular carcinoma (HCC) cells, and it also exhibits anticancer effects against HCC. The resulting GA-NG exhibited excellent biocompatibility. GA-NG formed stable complexes with survivin ASO and effectively shielded them from nuclease degradation. Moreover, GA modification enabled the GA-NG to significantly enhance the cellular uptake of survivin ASO in HepG2 cells through GA receptor-mediated endocytosis, thereby potentiating apoptotic cell death. The GA-NG/ASO effectively suppressed tumor growth by downregulating survivin expression, demonstrating potent gene silencing efficacy with no systemic toxicity. This work highlights the promising potential of GA-NG/ASO for targeted gene therapy against hepatocellular carcinoma.