Targeted Nanoparticle-Mediated Gene Therapy Mimics Oncolytic Virus for Effective Melanoma Treatment

摘要

Oncolytic virus has potential applications in cancer therapy. However, its clinical application is restricted by the virus-associated biosafety issues. Here, inspired by the key role of vesicular stomatitis virus matrix protein (VSVMP) in the oncolytic vesicular stomatitis virus (VSV) induced apoptosis, a targeted nanoparticle-delivered neutral VSVMP gene formulation is designed to act like the VSV for cancer therapy. This VSVMP formulation consists of a CRGDKGPDC peptide modified hybrid monomethoxy poly (ethylene glycol)-poly(d,l-lactide) nanoparticles complexed with VSVMP plasmid, having good blood compatibility and tumor targeting ability. The transfection efficiency is as high as that of VSV. After intravenous administration, the VSVMP formulation can efficiently target the tumor, significantly inhibit the melanoma growth and metastasis, prolong the survival time of tumor-bearing mice, and does not cause obvious systemic toxicity. The anticancer mechanisms involve apoptosis induction, angiogenesis inhibition and some virus-associated signal pathways activation. This work demonstrates a VSV-inspired nonviral gene therapy that has promising clinical applications in melanoma treatment.