Recent development of gene therapy for pancreatic cancer using non-viral nanovectors.

Pancreatic cancer (PC), characterized by its dense desmoplastic stroma and hypovascularity, is one of the most lethal cancers with a poor prognosis in the world. Traditional treatments such as chemotherapy, radiotherapy, and targeted therapy show little benefit in the survival rate in patients with advanced PC due to the poor penetration and resistance of drugs, low radiosensitivity, or severe side effects. Gene therapy can modify the morbific and drug-resistant genes as well as insert the tumor-suppressing genes, which has been shown to have great potential in PC treatment. The development of safe non-viral vectors for the highly efficient delivery of nucleic acids is essential for effective gene therapy, and has been attracting much attention. In this review, we first summarized the PC-promoting genes and gene therapies using plasmid DNA, mRNA, miRNA/siRNA-based RNA interference technology, and genome editing technology. Second, the commonly used non-viral nanovector and theranostic gene delivery nanosystem, especially the tumor microenvironment-sensitive delivery nanosystem and the cell/tumor-penetrating delivery nanosystem, were introduced. Third, a combination of non-viral nanovector-based gene therapy and other therapies, such as immunotherapy, chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT), for PDAC treatment was discussed. Finally, a number of clinical trials have demonstrated the proof-of-principle that gene therapy or the combination of gene therapy and chemotherapy using non-viral vectors can inhibit the progression of PC. Although most of the non-viral vector-based gene therapies and their combination therapy are still under preclinical research, the development of genetics, molecular biology, and novel vectors would promote the clinical transformation of gene therapy.