Gene Therapy with Enterovirus 3 C Protease: A Promising Strategy for Various Solid Tumors

Area of Science:

• Oncology
• Gene Therapy
• Molecular Biology

Background:

• Current cancer gene therapies primarily leverage antitumor immunity.
• There is a critical need for alternative mRNA cargoes that exert direct antitumor effects to broaden therapeutic options.

Purpose of the Study:

• To investigate the potential of lipid nanoparticles (LNPs) carrying messenger RNA (mRNA) encoding a viral 3C protease as a direct antitumor therapeutic.
• To evaluate the efficacy of this approach in various solid tumor models.

Main Methods:

• Lipid nanoparticles (LNPs) were engineered to carry mRNA encoding the viral 3C protease.
• The 3C-LNPs were administered via intracranial, subcutaneous, and intravenous injections in different solid tumor models.
• Tumor growth, survival, and angiogenesis were assessed.
• Mass spectrometry and cleavage site prediction assays were used to identify protease targets.

Main Results:

• Intracranial injection of 3C-LNPs significantly inhibited tumor growth and prolonged survival in glioblastoma models.
• Subcutaneous injection reduced tumor volume and inhibited angiogenesis in a breast cancer model.
• Intravenous injection demonstrated tumor growth inhibition, reduced angiogenesis, and prolonged survival in hepatocellular carcinoma models.
• Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was identified as a primary target degraded by the 3C protease.

Conclusions:

• mRNA encoding viral 3C protease delivered via LNPs can selectively induce tumor cell apoptosis and suppress tumor growth.
• This approach demonstrates broad-spectrum antitumor activity across diverse solid tumor models.
• Viral protease mRNA represents a promising candidate for next-generation cancer gene therapies.