A role for peptides in overcoming endosomal entrapment in siRNA delivery — A focus on melittin

Abstract

siRNA has the possibility to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 20 years of research dedicated to translating siRNA from a research tool into a clinically relevant therapeutic, minimal success has been had to date. Access to RNA interference machinery located in the cytoplasm is often overlooked, but must be considered when designing the next generation of siRNA delivery strategies. Peptide transduction domains (PTD) have demonstrated moderate siRNA transfection, which is primarily limited by endosomal entrapment. Strategies aimed at overcoming endosomal entrapment associated with peptide vectors are reviewed here, including osmotic methods, lipid conjugation, and fusogenic peptides. As an alternative to traditional PTD, the hemolytic peptide melittin exhibits the native capacity for endosomal disruption but causes cytotoxicity. However, appropriate packaging and protection of melittin with activation and release in the endosomal compartment has allowed melittin-based strategies to demonstrate both in vitro and in vivo safety and efficacy. These data suggest that melittin's membrane disruptive properties can enable safe and effective endosomolysis, building a case for melittin as a key component in a new generation of siRNA therapeutics.

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

“…To circumvent the shortcomings of lipid carriers, we used a peptidic NP structure that represents the culmination of a number of specific sequence modifications to the amphipathic cationic peptide, melittin (12,36,37). In this present version of the peptide, the pore-forming capacity has been intentionally attenuated while still permitting membrane penetration, thus facilitating endosomal escape and coordinated release of siRNA into cytoplasm to avoid deactivation of therapeutic moieties (8,9,11,38). We have previously shown that these particles did not elicit any systemic or adaptive immune responses in an experimental model of rheumatoid arthritis (10).…”

Ligand-targeted theranostic nanomedicines against cancer

“…Endosomal escape can be achieved by adding fusogenic lipids, endosomal escape peptides, membrane disruptive polymers or lysosomotropic agents to the surface of the nanocarrier or with the cargo [284, 285]. For example, efficient delivery of siRNA or DNA during cell transfection is attained by incorporating fusogenic lipids, commonly cationic lipids, into liposomes.…”

Melittin, a Potential Natural Toxin of Crude Bee Venom: Probable Future Arsenal in the Treatment of Diabetes Mellitus

“…A number of reviews are available in the literature, which focused on the miscellaneous pharmacological effects of BV proteins [17,[29][30][31][32][33][34][35][36][37]. However, to date, reviews of the mechanisms by which BV contributes to the antidiabetic activity are currently not available.…”