Amphipathic peptoid transporters for protein and nanoparticle delivery

The development of efficient intracellular delivery vectors requires a precise balance between cellular uptake and minimal cytotoxicity. Here, we describe a series of cationic amphipathic peptoids designed to evaluate how sequence variation controls cell penetration and uptake. The peptoid series showed substantially higher cellular uptake than previously developed peptoid transporters, while subcellular localization varied across the series. Intracellular distribution was influenced by the type and positioning of hydrophobic residues relative to guanidinium-bearing Nbtg residues. Based on their balanced uptake and cytotoxicity profiles, peptoids 1 and 7 were selected for cargo delivery studies. Biotinylated analogs promoted cellular accumulation of FITC-labeled streptavidin, and peptoid-functionalized PLGA nanoparticles showed enhanced cellular uptake and accumulation in 3D tumor spheroids compared with unmodified or octaarginine-modified nanoparticles. We believe that these cell-penetrating amphipathic peptoids have potential for macromolecular cargo delivery and offer additional advantages, such as sequence tunability, synthetic versatility, and proteolytic stability.