An adeno-associated virus vector-based intracellular peptide delivery system for treating hepatocellular carcinoma with wild-type p53.

The inactivation of the p53 protein explains the incidence of approximately 50% of hepatocellular carcinoma (HCC) cases. As a key negative regulator, murine double minute 2 (MDM2) mediates the degradation of p53 protein. Therefore, targeting the p53-MDM2 protein-protein interaction (PPI) has become a promising therapeutic strategy for cancers with wild-type p53 (wtp53). The p53-MDM2 interaction inhibitor (PMI) has shown potential to restore p53 function by disrupting its interaction with MDM2, however, the therapeutic efficacy of the PMI is compromised due to its instability and low cell membrane permeability. In this study, a peptide gene delivery system, sc-SUR(447)-GFP-PMI-4, was developed using self-complementary adeno-associated virus (scAAV). This system enables tumor-specific expression of tetrameric PMI peptides under the control of the survivin promoter. The results revealed that PMI-4 genes delivered by sc-SUR(447)-GFP-PMI-4 were selectively expressed in tumor cells both in vitro and in vivo. The system demonstrated potential as a safe and effective therapeutic agent in an orthotopic xenograft hepatocellular carcinoma (HCC) model where it inhibited the degradation of the p53 protein. In conclusion, the study introduced an innovative systemic peptide delivery system in which peptides delivered by scAAVs effectively block tumorigenic intracellular PPIs, providing a promising strategy for cancer therapy.