Gene delivery system and application thereof in preparation of drugs for treatment of tumors

A method of manufacturing a gene delivery system for treating a malignant solid tumor of epithelial origin, the gene delivery system comprising a nucleic acid vector and a delivery vehicle, the method comprising:

• preparing the nucleic acid vector,
• preparing the delivery vehicle, and
• mixing the nucleic acid vector and the delivery vehicle to form the gene delivery system, wherein:
• the nucleic acid vector comprises a self-replicating RNA including a gene encoding an HNF4 alpha protein, the self-replicating RNA has or carries a 35-100 nt polyadenine tail and comprises an engineered alphavirus genome that includes a 5′-cap, a non-coding or untranslated region (5′ UTR), four genes encoding nonstructural proteins that enable RNA replication, a 26S subgenome promoter, the gene encoding the HNF4 alpha replacing structural protein sequences of the engineered alphavirus genome, and a 3′ non-coding or untranslated region (3′ UTR),
• the delivery vehicle comprises lipid-based nanoparticles, and
• the gene delivery system delivers the HNF4 alpha or the self-replicating RNA into tumor cells, induces differentiation of the tumor cells into normal mature cells, inhibits proliferation of the tumor cells, and/or induces apoptosis of the tumor cells.