Research Projects

Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide, and combinational drug therapy and immune therapy are potential solutions. Combinational gene therapy, targeting multiple cancer-causing genes, could be ideal for HCC treatment. Using 3-6 small RNAs (siRNA and miRNA) to target 3-6 genes simultaneously would increase HCC inhibition efficacy due to the synergistic effect from multiple gene drugs. Alnylam developed three siRNA-based drugs, ONPATTRO, GIVLAARI, and OXLUMO, which have been approved by the FDA. RNA-based drugs are expected to become the third milestone in pharmaceutics after small molecule and protein-based drugs. Guo et al. extensively studied RNA nanoparticles to deliver chemo and gene therapeutics to various cancer types, but the core RNA nanoparticles would be laborious and expensive. This proposal proposes targeted delivery of combinational gene drugs using RNA interference (RNAi) nanotechnology. Small RNA molecules (siRNA and miRNA) are conjugated into an RNAi nanoparticle, delivered to liver cancer cells specifically by tagging cell-specific triGalNAc ligands. A total of 6 RNAi molecules are selected to study against HCC, including three siRNAs targeting PLK1, PCSK9, & HSP47 and three miRNAs targeting MDR1, RTKN, and IRS. The nanoparticles are assembled into RNAi nanoparticles, resulting in 42 RNAi nanoparticles. All 42 RNAi nanoparticles will be screened against HepG2 cells in vitro for their ability to inhibit cell proliferation. The best out of all 42 RNAi nanoparticles will be studied for HCC tumor inhibition in mice xenograft models.