Nanoparticles Vector Can Screens Release Peptides For Efficient Gene Delivery

For many years, gene therapy has attracted the attention of scientists all over the world due to its nature of fundamentally treating diseases, in order to overcome genetic diseases such as cancer, diabetes, and multiple sclerosis. However, nucleic acid-based drugs, including transgene-containing plasmids, SiRNAs, antisense oligonucleotides, aptamers, and ribozymes, have not achieved the expected results in clinical trials. The reason is that some extracellular and intracellular barriers hinder the bioavailability of these drugs at their site of action. Therefore, a delivery system that can overcome these obstacles is necessary. Over the past few decades, scientists have developed viral and non-viral vectors to deliver genetic drugs into cells of the body. Among these delivery vectors, although the virus delivery system has high efficiency, it poses considerable immunological and safety concerns due to its own risk of infection. Therefore, non-viral vectors including polymers, metal nanoparticles and bio-based nanomaterials have been developed for the specific delivery of DNA drugs and other biomolecules to their targets. Because of the targeted modification on these vectors, the local concentration of the gene drug on the surface of the target tissue cells and the bioavailability of the cargo have been greatly improved. However, the intracellular pathway from the cell membrane to the nucleus is a relatively obvious rate-limiting step in the entire gene transfer process, which includes the extreme electrostatic repulsion between nucleic acids and cell membranes, the encapsulation of nucleosomes, the crowded cytoplasm and highly organized nuclear membrane. These all severely reduce the effectiveness of most synthetic vectors. Among the above-mentioned obstacles, endosome entrapment is the main intracellular obstacle to gene transmission. Gene-bearing drug carriers enter cells through endosome and are coated with endosomal vesicles to produce endosome, which later mature into lysosomes due to endocytosis. During endosome maturation, the decrease in pH in the vesicles and the activation of the nuclease can cause the degradation of the encapsulated nucleic acid drug. Therefore, the release of the nucleic acid vector before the endosome matures is a guarantee that the gene drug enters the nucleus for therapeutic purposes, otherwise the gene drug will be degraded.

With the deepening of the research on the process of nuclear endosome maturation and the mechanism of viral infection, scientists have discovered that the mechanism of viral infection to escape nuclear endosome can be used to complete the escape of gene drugs. Further research revealed that the reason why the virus can escape from endosomes is due to the presence of a release peptide on the virus, which is easily transferred from the endosome membrane. Therefore, researchers have conducted in-depth research on pH-sensitive influenza-derived H5WYG (HNH) and pH-insensitive AIDS-derived GP41 (GNH) in endosome release peptides. Researchers have designed peptide-based nanoparticles vectors by using genetic engineering techniques, and used fluorescent labels to evaluate their gene delivery capabilities. Through luciferase experiments, the researchers found that the transfection efficiency of HNH was twice that of GNH. Further comparison and tracking revealed that H5WYG has superior endosomal escape ability. Therefore, this nanoparticles carrier can be used to screen different endosomal release peptides, and select release peptides that can significantly improve gene delivery capabilities. Finally, the goal of efficient delivery of gene drugs is achieved.