Surface-engineering RNA nanoparticles for targeted and efficient hepatocellular carcinoma drug delivery

Chemotherapy is an anti-cancer treatment that uses chemical drugs to suppress rapidly growing cancer cells. Nevertheless, low water solubility and poor pharmacokinetics of chemotherapeutic drugs can reduce therapeutic efficacy and limit the duration of drug action due to rapid clearance from the body. Furthermore, systemic chemotherapy can attack not only cancer cells but also normal cells, inducing severe side effects. In this study, Tri-GalNAc-decorated RNA nanoparticles (RNAPs) loaded with doxorubicin (Dox-TG-RNAP) were developed to treat hepatocellular carcinoma (HCC). The surface of RNAP was decorated with avidin and biotin-Tri-GalNAc sequentially using electrostatic and non-covalent interactions. Dox-TG-RNAP had a high loading capacity of Dox and delivered Dox to HCC cells specifically through asialoglycoprotein receptor (ASGPR)-mediated endocytosis. Consequently, Dox-TG-RNAP induced apoptosis selectively in HCC cells expressing ASGPR, while minimizing cytotoxicity in non-ASGPR-expressing cells such as HDF cells. Such ligand-modified RNAPs facilitated targeted drug delivery effectively to a range of tissues through surface functionalization with diverse ligands, thereby mitigating off-target effects.