Novel fusion peptide-mediated siRNA delivery using self-assembled nanocomplex

Abstract

Background: Gene silencing using siRNA can be a new potent strategy to treat many incurable diseases at the genetic level, including cancer and viral infections. Treatments using siRNA essentially requires an efficient and safe method of delivering siRNA into cells while maintaining its stability. Thus, we designed novel synergistic fusion peptides, i.e., SPACE and oligoarginine.Results: Among the novel fusion peptides and siRNAs, nanocomplexes have enhanced cellular uptake and gene silencing effect in vitro and improved retention and gene silencing effects of siRNAs in vivo. Oligoarginine could attract siRNAs electrostatically to form stable and self-assembled nanocomplexes, and the SPACE peptide could interact with the cellular membrane via hydrogen bonding. Therefore, nanocomplexes using fusion peptides showed improved and evident cellular uptake and gene silencing of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) via the lipid raft-mediated endocytosis pathway, especially to the HDFn cells of the skin, and all of the fusion peptides were biocompatible. Also, intratumorally injected nanocomplexes had increased retention time of siRNAs at the site of the tumor. Finally, nanocomplexes demonstrated significant in vivo gene silencing effect without immunogenicity.Conclusions: The new nanocomplex strategy could become a safe and efficient platform for the delivery of siRNAs into cells and tissues to treat various target diseases through gene silencing.

Fusogenic peptide delivery of bioactive siRNAs targeting CSNK2A1 for treatment of ovarian cancer

“…Following tumor establishment, we examined whether the DIV3W peptide delivered siRNAs into ovarian tumor tissue. Similar to other peptide-siRNA carriers delivered via intratumoral injection into SQ tumors in mice, 9 , 59 our results revealed that the novel fusogenic peptide enhanced retention of siRNA in tumor tissue via intratumoral delivery in SQ tumors, demonstrating the stability of the complex and potential to prevent siRNA degradation. We also observed siRNA signal in organs of the mononuclear phagocytic system when treatment was administered via both IP and intratumoral routes.…”

Efficient and safe small RNA delivery to macrophage using peptide‐based nanocomplex

“…The final shRNA release percentages were expressed by considering the quantitative values of the free shRNA as 100%. The data represented mean ± standard deviation electrostatic interaction between positively charged amino acids and RNA (Ryu et al, 2021;Tai & Gao, 2017).…”

“…The siRNAs with particle-like fluorescence were distributed around the nucleus of the cell. After the endocytosis of nanocomplexes, the siRNAs escaped from the endosomal trap and were released from the nanocomplex, resulting in a spreading fluorescence (Chiu et al, 2004;Kim et al, 2010;Ryu et al, 2021;Wang et al, 2007Wang et al, , 2014.…”

“…Therefore, in this study, the unique p19 subunit of IL-23 was selected as a target. The previous study devised a novel fusion peptide-mediated nanocomplex system without additional covalent bonding (Ryu et al, 2021). We demonstrated an efficient siRNA delivery system to cancer cells mediated by nanocomplex.…”

Targeted Delivery of siRNA through Nanocomplex using Specific Fusion Peptides for Breast Cancer Treatment

“…[21] Furthermore, because it has a positive charge, it neutralizes the negative charge of nucleic acids and facilitates intracellular transfer through hydrogen bonding with the cell membrane. [22][23][24][25] However, polyarginine-based carriers cannot deliver drugs targeting certain cell types. So, the non-targeted delivery of cytotoxic drugs can cause various side effects, i.e., damage to normal tissues.…”