The nanotube express: Delivering a stapled peptide to the cell surface

Hypothesis: Carbon nanotubes (CNTs) represent a novel platform for cellular delivery of therapeutic peptides. Chemically-functionalized CNTs may enhance peptide uptake by improving their membrane targeting properties. Experiments: Using coarse-grained (CG) molecular dynamics (MD) simulations, we investigate membrane interactions of a peptide conjugated to pristine and chemically-modified CNTs. As proof of principle, we focus on their interactions with PM2, an amphipathic stapled peptide that inhibits the E3 ubiquitin ligase HDM2 from negatively regulating the p53 tumor suppressor. CNT interaction with both simple planar lipid bilayers as well as spherical lipid vesicles was studied, the latter as a surrogate for curved cellular membranes. Findings: Membrane permeation was rapid and spontaneous for both pristine and oxidized CNTs when unconjugated. This was slowed upon addition of a noncovalently attached peptide surface sheath, which may be an effective way to slow CNT entry and avert membrane rupture. The CNT conjugates were observed to desheath their peptide layer at the bilayer interface upon insertion, leaving their cargo behind in the outer leaflet. This suggests that a synergy may exist to optimize CNT safety whilst enhanc-ing the delivery efficiency of hitchhiking therapeutic molecules. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Hypothesis: CNTs can be a platform for cellular delivery of therapeutic peptides, and chemically-modified CNTs can enhance peptide uptake. The addition of a peptide surface sheath can slow membrane permeation, and CNT conjugates can desheath their peptide layer at the bilayer interface to potentially enhance therapeutic molecule delivery efficiency.