(338d) Engineering MS2 Bacteriophage Virus-like Particle for Targeted Drug Delivery into Hepatocellular Carcinoma.

Hepatocellular carcinoma, comprising 90% of liver cancers, exhibits a dismal five-year survival rate of 30%. Current treatment confronts limitations such as drug resistance and severe side effects. Nanotechnology, particularly Virus-Like Particles (VLPs), are a promising avenue for delivering therapeutics exclusively into the liver through targeted drug delivery, reducing side effects and enabling advanced treatments, such as gene therapy. To this end, we identified and engineered targeted drug delivery nanocarriers based on the native bacteriophage MS2 VLP. Initially, we screened sixteen MS2 VLP mutants that are assembly competent and contain an externally facing cysteine that could be conjugated with targeting ligands of interest via maleimide-thiol conjugation. Next, we selected variants that maintain the capsid quaternary structure after undergoing conjugation with maleimide-GalNAc, the ligand that binds to ASGPR receptors predominately encountered in hepatocytes. Finally, we demonstrated that MS2 VLP-GalNAc constructs are selectively internalized by cells that express ASGPR receptors. This research aims to advance the development of MS2 VLPs as a versatile platform for targeted drug delivery and the research outcomes are foundational for advances in therapeutic interventions for hepatocellular carcinoma.